Institute of Medical Technology

Institute of Medical Technology

Annual Report 2010 Institute of Medical Technology University of Tampere 1 INDEX Foreword...

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Annual Report 2010

Institute of Medical Technology University of Tampere

1

INDEX Foreword...........................................................................

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About IMT IMT Personnel.................................................................. IMT Board and Scientific Advisory Board...................... IMT Administration.........................................................

6 7 8

Strategy, Mission, Vision................................................. Research programs..........................................................

10 11

Research groups Bioinformatics................................................................. Protein Dynamics Group................................................ Molecular Biotechnology................................................ Cancer Biology................................................................ Cancer Genomics............................................................ Genetic Cancer Predisposition........................................ Molecular Biology of Prostate Cancer............................. Biochemistry of Cell Signaling........................................ Cell Interactions............................................................... Mitochondrial Gene Expression and Disease.................. Mitochondrial Biogenesis in Health and Disease............ Mitochondrial Gerontology and Age-related Diseases.... Mitochondrial DNA Maintenance................................. Genetic Immunology....................................................... Immunoregulation........................................................... Experimental Immunology.............................................. Molecular Immunology................................................... Coeliac Disease............................................................... Tissue Biology.................................................................

12 14 16 17 19 20 21 22 24 25 27 28 29 30 32 33 34 35 37

Education Biotechnology program................................................... Master’s Degree Program in Bioinformatics................... Tampere Graduate Program in Biomedicine and Biotechnology.................................................................

IMT Annual Report 2010 Publisher Institute of Medical Technology 2011 Editor Tapio Visakorpi, Professor Sub-editor Jaana Salmensivu-Anttila, Administrator Photographs All IMT Research Groups Jukka Lehtiniemi Front-page image “1DDZ” by Martti Tolvanen Page layout Jukka Lehtiniemi, ADP

38 39 40

All publications 2010........................................................ 42

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Institute of Medical Technology

Annual Report 2010

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Foreword, IMT 1995-2010 As from the beginning of 2011 IMT will be the central part of the Institute of Biomedical Technology, so this will be the last Annual Report from IMT. The new institute will consist of units operating in biomedical and translational research and its exploitation, and will offer universities in Tampere Region an excellent opportunity to develop a high quality interdisciplinary center ready to meet present and future challenges. IMT was a success story. Fifteen years ago a few scientists were brought into an empty building in the middle of Kauppi forest, and that initiative developed into an international high quality research and education center. I want to thank all our personnel over the years; you made this happen. The founder Prof. Kai Krohn, our collaborators and supporters are all warmly thanked.

From IMT photograph arc

hives

It is our duty to ensure that the legacy of IMT in high quality research and education will flourishes and develops further in the new institute. Olli Silvennoinen

4

Institute of Medical Technology

Annual Report 2010

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IMT Personnel IMT consists of fifteen research groups and two affiliated groups with a total staff of some 180. This includes project leaders, senior and post-doctoral researchers, PhD students, laboratory technicians and other personnel. About 67% of the staff iareacademic scientists, 26% research support staff while 7% work in administration. About 20% of the personnel are foreigners. The major resource of IMT is professionally skilled, highly educated and motivated personnel. The Institute is committed to developing the working environment for all its employees. Integral parts of the personnel policy are providing a good working environment, career development opportunities a rewarding system of remuneration and addressing equal opportunity issues. Continuing education is provided for the entire personnel. The IMT personnel can participate in activities intended to maintain working ability including support for sporting activities. In addition the Institute has its own bi-annual event to promote well-being at work and foster team spirit. The research strategies and institutional policies are openly discussed at monthly group leader meetings, thereby providing an opportunity for all scientists to influence the decisions and strategies. Institutional policies and recruitment strategies are also discussed at IMT staff meetings providing an opportunity for all personnel to participate in the decision-making.

Members of the Board 1.1.2010-31.12.2010









(Primary member, position and personal deputy member)

Nordback Isto, Chairman, Director, Division of surgery, gastroenterology and oncology, TAUH Turjanmaa Väinö, MD, Tauh Prof. Kallioniemi Anne, IMT Prof. Visakorpi Tapio, IMT Prof. Kulomaa Markku, IMT Prof. Parkkila Seppo, IMT Prof. Isola Jorma, IMT Prof. Vihinen Mauno, IMT Prof. Hurme Mikko, Faculty of Medicine Skottman Heli, Senior Researcher, Regea Rovio Anja, Project Manager, IMT Schleutker Johanna, Principal Investigator, IMT Hinkka Janette, Laboratory technician, IMT Valanne Susanna, Research Fellow, IMT Wahlfors Jarmo, Research Development Director, University of Tampere Salminen Tiina, Project manager, University of Tampere Uusi-Rajasalo Harri, City of Tampere Tainio Hanna, Medical Advisor, MD, PhD, City of Tampere Eskola Matti, Managing director, Finn-Medi Research Valimaa Tero, Director, Finn-Medi Research Ojala Elina, Student Siivonen Joonas, Student Prof. Silvennoinen Olli, Presenting official Salmensivu-Anttila Jaana, Administrator, Secretary

6

IMT Administration

SAB Scientific Advisory Board

IMT is led by a ten-member Board representing the University of Tampere and surrounding institutions, such as the City of Tampere, Tampere University Hospital (TAUH) and biotechnology companies. The Board also includes representation of professors, other personnel and the students of IMT. The Director serves the presenting official for the Board and is responsible for most of the research-related and administrative decisions. IMT’s administration consists of a laboratory chief, a coordinator and an amanuensis (MSc program), an administrator, a financial assistant and clerical staff.

The Scientific Advisory Board consists of four distinguished scientists. The duties of the SAB are to issue statements on the competence of applicants for the post of director, to evaluate the scientific programs of the Institute and rolling tenure track professors, and to formulate initiatives and provide statements on new research programs.

Institute of Medical Technology

Annual Report 2010

Prof. Carl-Henrik Heldin, Ludwig Institute for Cancer Research, Uppsala, Sweden Prof. Marja Jäättelä, Danish Cancer Society, Copenhagen, Denmark Prof. Juha Kere, Department of Biosciences and Nutrition, Novum, Huddinge, Sweden Prof. Kjetil Taskén, The Biotechnology Centre of Oslo, Oslo, Norway

7

Funding 2010 External funding Ministry of education and Univ.of Tampere

10

Administrative personnel 2010

8

Administrator Jaana Salmensivu-Anttila Coordinator Marjatta Viilo Amanuensis Riitta Aallos

4

2

53% 21% 7% 6% 6% 4% 3%

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

0 1996

Total 11,5 m€

6

1995

Laboratory chief Anja Rovio

Million euros

Director Olli Silvennoinen, Director Tapio Visakorpi, Vice Director

Budget Academy of Finland Biocenter Finland European Union Foundations EVO Own Income Financing, University Alliance, etc.

Financial Affairs Kaarin Forsman Departmental Secretary Suvi-Elina Kalliola Erika Säynässalo (16.8.2010 -)

Personnel 2010

Office Secretary Maria Bergman, Office Secretary -28.2.2010

180

Study Secretary Mira Pihlström

120

Academic researchers Research support staff Administration

160 140

100 80 60

20

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

1996

0

1995

Staff altogether 171 persons

40

73% Researchers 21% Support staff 6% Administration

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Institute of Medical Technology

Annual Report 2010

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Research Programs

Strategy, Mission, and Vision The IMT strategy for the years 2006 – 2010 sees the Institute as a modern, internationally competitive research and teaching institute of the University of Tampere. The main focuses are medical technology and biotechnology. The Institute’s role as a developer of the above- mentioned focus areas is the principaltheme of our strategy. Developing of high quality biomedical and biotechnology research and teaching is our mission. Our Institute is a dynamic research and education institution, where synergistic research and teaching areas lay the foundations for modern multidisciplinary research projects and commercial applications. The main aim is to integrate education, research and development into a tight unity where the three different aspects support each other.

The FinMIT Centre of Excellence, based in IMT and in Biomedicum Helsinki, was recently granted on extension for a further six years, from 2008 to 2013, under the title ‘Centre of Excellence in Research on Mitochondrial Disease and Ageing’. FinMIT combines the efforts of four research groups, those of Hans Spelbrink and Howy Jacobs in IMT Tampere, and of Brendan Battersby and Anu Suomalainen in Biomedicum Helsinki, to develop new knowledge about the role of mitochondria in human disease, including the degenerative diseases of old age, and to use this knowledge to develop novel diagnostic and therapeutic tools for the benefit of patients and their families. The work is undertaken primarily using model organisms such as Drosophila and the zebrafish, but also involves the analysis of clinically derived cell-lines and DNAs, and the use of in vitro systems to better understand the biochemistry of mitochondrial function. The Translational Prostate Cancer Research Program (TPCRP) was established on the campus of the University of Tampere and Tampere University Hospital (TAUH) in the early 1990’s. Today, the core of TPCRP consists of three research groups: Genetic Predisposition to Prostate Cancer (GPPC), led by Professor Johanna Schleutker; the Molecular Biology of Prostate Cancer group (MBPCG), led by Prof. Tapio Visakorpi; and the Department of Urology (DoU), led by Prof. Teuvo Tammela. The overall aim of the TPCRP is to form close interactions between basic scientists and clinicians to provide an excellent basis for translational research and education. The unique collection of population-based clinical materials and models with complementary expertise provides exceptionally good preconditions to study prostate cancer. Special emphasis is placed on the training of basic scientists and clinicians so that they understand each other and to foster their clinical researcher careers. Vactia - The Center for Vaccine Research and Immunology. Vaccine development and immunology have been recognized as strategic competence areas of the University of Tampere. Tampere is the leader in vaccine research in Finland. For example, the largest trials in Finland studying the efficacy of vaccines are conducted by the Vaccine Research Center. In order to develop vaccine research further in Tampere, key operators in the field have joined forces to create Vactia – The Center for Vaccine Research and Immunology. The founding members of Vactia include the Vaccine Research Center, the Department of Virology, Finn-Medi Research, the Institute of Medical Technology, STD-Vaccine Research, Fit Biotech and Vactech. In total, Vactia includes of nearly 200 researchers and aims to promote vaccine development – from basic research to clinical trials – and to facilitate the establishment of new spin-off companies.

Biocenter Finland Funded Core Facilities The University of Tampere Drosophila Core facility, funded by Biocenter Finland, is a facility promoting the use of the model organism Drosophila melanogaster in life sciences. The services offered by the Drosophila core facility include obtaining transgenic flies of interest, consultation and guidance on the experimental setting, and ordering and maintenance of fly lines. More information can be found at: http://cofa.uta.fi/drosophila_index.php University of Tampere Zebrafish Core facility, funded by Biocenter Finland, serves all scientists using zebrafish as a research model system. The new facility is capable of housing up to 50,000 adult zebrafish. Zebrafish provide a vertebrate model where many advantages of lower invertebrate model organisms are combined with the benefits of mammalian research models. Such advantages include embryonic development ex utero, transparency of embryos and rapid embryonic development. Zebrafish core facility services include e.g. housing of zebrafish, morpholino injections and F3 homozygous mutant carrier families for genetic screening. More info at: http://cofa.uta.fi/zebra_index.php

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Institute of Medical Technology

Annual Report 2010

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Bioinformatics The goal of the Bioinformatics Group is to understand biological and medical phenomena at the structural, mechanical and systems level by applying and developing bioinformatics tools and applications. The Group has two major research lines. Analysis and prediction of the effects of variations ranges from collecting information into publicly accessible databases to detailed structural and functional studies of the effects and consequences of the variations. Currently we maintain about 140 variation databases (http://bioinf.uta.fi/). These databases mainly contain information on immunodeficiencies and cancers. The effects and consequences of the variations are investigated at RNA, DNA and protein level. The ultimate goal is to help in developing new therapies to treat patients. We are developing tools for the prediction of numerous effects on protein structure, function, interactions, stability, aggregation and disorder propensity etc. For this purpose we provide the Pathogenic-Or-Not-Pipeline (PON-P), that allows easy and fast access to a large number of predictors and interpretation of the predictions. We have successfully predicted the effects of thousands of variations. We have also investigated the performance of numerous prediction methods with large test sets. For these studies we have collected benchmark datasets in VariBench, a suite for high-quality experimentally verified variation information.

Bioinformatics The aim of the Bioinformatics Group is to understand biological and medical phenomena in structural, mechanical and systems level by applying bioinformatics tools and applications.

The other research line is systems biology of the immune system. We have identified genes and proteins essential to human immunity. The evolution of these genes and proteins has been investigated and a database generated for about 1,500 proteins. These datasets allow system wide analysis of immunity. We have investigated and simulated certain immunological processes based on immunome interactome (protein-protein-interactions) and gene expression information. These studies have revealed new features of biological networks and allowed e.g. successful prediction of novel primary immunodeficiency (PID) candidate genes. Another approach to investigating the immune system at system level is to follow gene and protein expression during B-cell development by applying microarray and proteomics methods. We are now applying systems immunological approaches to study the mechanisms of PIDs to learn how these diseases could be efficiently treated on system level. Main collaboration Professor Tapio Salakoski, Deparment of Information Technology, University of Turku, Finland; Professor Harri Savilahti, Department of Biology, University of Turku, Finland; Professor C. I. Edvard Smith, Karolinska Institutet, Stockholm, Sweden; Human Genome Variation Society board members; Immunodeficiency diagnostic and research laboratories; European Bioinformatics Institute. Funding Academy of Finland, Medical Research Fund of Tampere University Hospital, Sigrid Juselius Foundation, Biocenter Finland. Personnel Group Leader: Post-doctoral Fellow: PhD Students:

Undergraduate Students:

Other staff:

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Institute of Medical Technology

Annual Report 2010

Professor Mauno Vihinen, PhD Csaba Ortutay, PhD Sofia Khan, MSc Johanna Salonen, MSc Crina Samarghitean, MD, MSc Janita Thusberg, MSc Jouni Väliaho, MSc Heidi Ali Ayodeji Olatubosun Preethy Nair Jani Härkönen Sreevani Kotha Percy Nutifafa Hevor Abhishek Niroula Saija Sorsa Martti Tolvanen, PhLic Hannu Korhonen, system manager

13

Protein Dynamics Group Conformational changes in proteins are important for protein function, including ligand recognition, protein-protein interactions and chemical modifications of proteins. The Protein Dynamics Group uses experimental and computational methods to elucidate the importance of changes in protein conformation and protein interactions caused by mechanical stress. Our major focus is to on exploring the structural dynamics of the proteins in cellular adhesion sites called focal adhesions. We are focus particularly on talin and vinculin, two proteins in the complex that connects the actin cytoskeleton to the integrin receptors on the cell surface. We also engage in material research to develop novel biosensors and better tools for gene transfer. In addition, we participate in research focusing on avidin-biotin technology in collaboration with Professor Kulomaa. The experimental tools include recombinant proteins and mutagenesis, interaction analysis methods, fluorescence spectroscopy and optical microscopy. Computational biology makes it possible to understand the protein behavior at atomic resolution, and we use molecular dynamics simulations as a main tool. Biocenter Finland plays an important role in our operation and we provide services in protein production and protein analysis.

Biotechnology

Main collaborators

The biotechnology groups study and engineer proteins to understand their structure-function relationships and to apply them in diagnostics, vaccination and materials science

Professors Mark S. Johnson and J. Peter Slotte, and Docent Tomi Airenne, Åbo Akademi University; Professor Janne Jänis, Dr. Maija Lahtela-Kakkonen and Dr. Mikael Peräkylä, University of Eastern Finland; Professor Janne Ihalainen, Docents Maija Vihinen-Ranta and Jussi Toppari, University of Jyväskylä; Professor Kristiina Takkinen, VTT Technical Research Center of Finland, Espoo; Docent Perttu Permi, University of Helsinki; Professors Seppo Parkkila, Timo Vesikari and Heikki Hyöty, University of Tampere. Professor Oded Livnah, Hebrew University of Jerusalem, Israel; Professor Viola Vogel, ETH Zürich, Switzerland; Dr. Bernhard Wehrle-Haller, University of Geneva, Switzerland, Professor Peter Hinterdorfer, Dr. Andreas Ebner and Dr. Hermann Gruber, Johannes Kepler Universität Linz, Austria   Funding Academy of Finland, Biocenter Finland, Sigrid Jusélius Foundation, Health District of Pirkanmaa, The National Graduate School in Informational and Structural Biology (ISB) Personnel Group Leader: Post-doctoral Fellows: PhD Students: Undergraduate Students: Laboratory staff:

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Institute of Medical Technology

Annual Report 2010

Docent Vesa Hytönen, PhD Juha Määttä, PhD Jenita Pärssinen, PhD Sampo Kukkurainen, MSc Barbara Niederhauser, MSc Henrik Hammarén Joonas Siivonen Outi Väätäinen

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Molecular Biotechnology Group Protein engineering and protein design followed by the many sided analyses of the functional and structural properties of the products are the major experimental approaches in the Molecular Biotechnology (MBT) Group in IMT. Bacterial and eukaryotic expression systems are used to produce the recombinant proteins, and site-directed and random mutagenesis (phage display, DNA-shuffling) for genetic modification of the proteins. Functional characterization of the proteins engineered and their interactions, particularly with small ligands, are performed using a wide variety of biochemical and biophysical methods. They include, for instance, surface plasmon resonance (SPR), optical biosensors (Biacore), fluorescence spectroscopy, isothermal titration (ITC) and differential scanning (DSC) calorimetry, atomic force microscopy (AFM), and light scattering analyses. Computational methods, for example molecular modeling and molecular dynamics simulations, are also used in protein design and analysis. Structural analysis of the engineered proteins by X-ray crystallography, NMR, and cryo-EM is performed by our national and international collaborators. The research in the MBT group focuses on four topics: 1. Engineering of biotin-binding proteins, aiming at the development of novel protein tools for bio- and nanotechnology. This includes the development of avidins carrying heterogenous binding sites in a single molecule, the development of novel ligands for avidins, and the engineering of avidins with efficient immobilization capabilities. 2. Production and characterization of virus proteins and virus-like particles for the development of diagnostics and vaccines. 3. Use of biological macromolecular building blocks for the development of improved and new biofunctional nanostructures. 4. Design and production of ultra sensitive, stable and easy to use atomic force spectroscopy (AFM) biosensor tips (Intellitip). Docent Vesa Hytönen was appointed Group Leader position in IMT, and therefore, started his own Protein Dynamics (PD) Group at beginning of August, 2010. Three other scientists and a technician moved with him from the MBT group to the PD group. However, active collaboration between our groups continues. We use the same laboratory facilities and technical approaches and hold group meetings together. Main collaborators

Cancer Research

The cancer research groups aim to identify the molecular mechanisms of cancer and translate the information into new clinical tools.

Professors Mark S. Johnson and J. Peter Slotte, and Docent Tomi Airenne, Åbo Akademi University; Professors Janne Jänis, Seppo Ylä-Herttuala and Kari Airenne, Dr. Maija Lahtela-Kakkonen and Dr. Mikael Peräkylä, University of Eastern Finland; Professors Kari Rissanen, Docents Maija Vihinen-Ranta, Varpu Marjomäki, University of Jyväskylä; Professor Kristiina Takkinen, VTT Technical Research Center of Finland, Espoo; Docent Perttu Permi, University of Helsinki; Professors Seppo Parkkila, Timo Vesikari and Heikki Hyöty, University of Tampere. Professor Oded Livnah, Hebrew University of Jerusalem, Israel; Professors Meir Wilchek and Edward Bayer, Weizmann Institute of Sciences, Rehovot, Israel; Professor Viola Vogel, ETH Zürich, Switzerland; Professor Peter Hinterdorfer and Dr. Andreas Ebner, Johannes Kepler Universität Linz, Austria; Professor Peter Schurtenberger, Drs. Herve Dietsch and Christian Moitzi, University of Fribourg, Switzerland.  Funding Academy of Finland, The Finnish Funding Agency for Technology and Innovation (TEKES), MNT-ERA.net, Health District of Pirkanmaa, The National Graduate School in Informational and Structural Biology (ISB), and Tampere Graduate School in Biomedicine and Biotechnology (TGSBB). Personnel Group Leader: Post-doctoral Fellows:

PhD Students:

16

Professor Markku Kulomaa, PhD Docent Vesa Hytönen, PhD (until 31.7.2010) Satu Helppolainen, PhD (until 28.2.2010) Anssi Mähönen, PhD Juha Määttä, MSc, PhD 18.6.2010 (until 31.7.2010) Tiina Riihimäki, MSc Tiia Koho, MSc Jenni Leppiniemi, MScEng Barbara Niederhauser, MSc (until 31.7.2010) Sampo Kukkurainen, MSc (until 31.7.2010) Soili Hiltunen, MSc

Institute of Medical Technology

Undergraduate Students:

Laboratory staff:

Annual Report 2010

Other staff:

Suvi Varjonen Selina Mäkinen Toni Grönroos Elina Ojala Ulla Kiiskinen, technician Tanja Heinonen (Vactech Oy) Joanna Zmurko, work placement student (Univ. Glasgow) Tuomas Mäntylä, MSc

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Cancer Biology

Cancer Genomics

Trastuzumab is a recombinant monoclonal antibody drug that is widely used in the treatment of breast cancer. Despite encouraging clinical results, some cancers are primarily resistant to trastuzumab, and a majority of these initially responding become resistant during prolonged treatment. We have previously established an experimental research model for trastuzumab resistance (cell line JIMT-1) by using cells from a drug-resistant patient. JIMT-1 cells are intrinsically resistant to trastuzumab in vitro, but the direct mechanism(s) for drug resistance remains uncertain, despite numerous published reports by us and other groups.

Breast and pancreatic cancers are among the most common causes of cancer deaths in industrialized countries and thus constitute an important cause of morbidity and mortality. The main focus of the Cancer Genomics Research Group is the identification of genes and molecular pathways that are critical for the development and progression of these tumor types, as they are likely to provide new diagnostic tools or therapeutic targets for the clinical management of breast and pancreatic cancer.

Although it has been reability documented that trastuzumab inhibits mitotic and apoptotic signaling via cell surface receptor tyrosine kinases, an increasing number of studies suggest that the main mechanism of action is mediated by the lymphocytic immune reaction evoked by trastuzumab bound to the cancer cells. We have recently shown that immune effector cells (mainly natural killer T lymphocytes) react equally well in breast cancer cell lines irrespective of the direct resistance in mitotic cell signaling (Barok et al.). The immune mechanisms are likely to be more important in the treatment of early (submacroscopic but disseminated) cancer, which is the best target for anti-HER2 therapy. We aim to monitor CTCs and DTCs in our xenograft mouse tumor models, and study whether trastuzumab has an inhibitory effect on CTCs and DTCs at the time when the primary tumor has already grown too large to be growth-inhibited by trastuzumab and the immune system. According to our hypothesis, single tumor cells shed into the blood stream may differ in their trastuzumab sensitivity, since there are no surrounding connective tissue glycosaminoglycans and/or other cell surface molecules responsible for epitope masking. These studies are intended to form an experimental basis for the molecular diagnostics of circulating HER-2 positive tumors cells. Our research also includes medical imaging and virtual microscopy (i.e., viewing and handling digitized microscope specimens with computers). We have developed free image software tools for automated scanning, analysis, viewing, network transmission, and clinical DICOM linkage (Tuominen et al.). Please see our website for more details: http://jvsmicroscope.uta.fi/. Main collaborators University of Helsinki, Department of Oncology & Biomedical Informatics Group; University of Lund, Department of Oncology, Sweden; University of Debrecen, Hungary. Funding The Finnish Cancer Foundation, Sigrid Juselius Foundation and Medical Research Fund of Tampere University Hospital (EVO). Personnel Group Leader: Post-doctoral Fellows:

PhD Students:

Undergraduate Student: Laboratory staff:

Other staff:

18

In pancreatic cancer, we are focusing our efforts on the study of genes that are activated through DNA amplification during cancer pathogenesis. To this end, we have applied a combination of high-throughput microarray based screening techniques and traditional positional cloning methods to identify regions of the genome that are commonly amplified in pancreatic cancer cell lines and to pinpoint actual putative amplification target genes. The functional role of these genes in cancer development is then studied in cell line model systems. The possible clinical significance of these newly identified molecular targets is being evaluated in a large series of pancreatic cancer patients using tissue microarray technology. Together these studies aim at elucidating the possible contribution of the putative amplification target genes to pancreatic cancer pathogenesis. Main collaborators Professor Daniel von Hoff, University of Arizona, USA; Drs. Spyro Mousses and David Azorsa, Translational Genomics Research Institute, AZ, USA; Professor Guido Sauter, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Dr. Sampsa Hautaniemi, Computational Systems Biology Laboratory, Institute of Biomedicine, University of Helsinki, Finland; Dr. Reija Autio, Signal Processing Unit, Tampere Technical University, Finland; Professor Kaija Holli, Medical School, University of Tampere, Finland; Dr. Heini Huhtala, School of Public Health, University of Tampere, Finland. Funding The Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cancer Organizations, the Medical Research Fund of Tampere University Hospital, the National Institutes of Health (USA). Personnel

Professor Jorma Isola, MD, PhD Minna Tanner, MD, PhD, Docent Mark Barok, MD, PhD Synnöve Staff, MD, PhD Jukka Pitkänen, MD, PhD

Group Leader: Post-doctoral Fellows:

Katri Köninki, MSc Vilppu Tuominen, MSc Teemu Tolonen

PhD Students:

Laura Partanen

Undergraduate Students:

Kristiina Ryömä, Bioanalyst Sari Toivola, Laboratory technician Eeva Pesonen, Bioanalyst

Laboratory staff:

Ulla Saarela, Coordinator

Institute of Medical Technology

In breast cancer, we are exploring the role of bone morphogenetic proteins, especially BMP4 and BMP7, in cancer development. BMPs are extracellular signaling molecules that control various cellular processes, such as proliferation, differentiation, apoptosis and migration by regulating target gene transcription. They have essential roles during embryogenesis and organogenesis but are also implicated in cancer pathogenesis. We are studying the functional relevance of BMP4 and BMP7 signaling in breast cancer by using well-established breast cancer cell line model systems. Using large tumor materials we are also evaluating the clinical significance of various BMP signaling pathway components and thereby the possible clinical utility of these molecules in breast cancer.

Annual Report 2010

Professor Anne Kallioniemi, MD, PhD Kimmo Savinainen, PhD Emma-Leena Alarmo, PhD Alejandra Rodriguez Martinez, PhD Johanna Ketolainen, MSc Riina Kuuselo, MSc Eeva Laurila, MSc Laura Rantanen Minna Ampuja Riikka Laurila Kati Rouhento, Technician

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Genetic Cancer Predisposition

Molecular Biology of Prostate Cancer Group (MBPCG)

Genetics seem to have a major role in susceptibility to cancer. Although the actual inherited cancer syndromes cause only about 1% of all cancers, a much greater proportion of the overall cancer risk may be explained by heritable factors. For prostate and breast cancer – the most common cancers in males and females – the repective estimates are 42% and 27%. Genes found to be affected in hereditary cancers can lead to the discovery of new pathways and processes relevant to carcinogenesis. These genes can also be inactivated by somatic mutation or epigenetic modification in sporadic cancers.

The Molecular Biology of Prostate Cancer Group (MBPCG) studies somatic genetic alterations in prostate cancer with emphasis on alterations associated with disease progression. Finding the common genetic alterations is an important step in the development of better diagnostics and therapeutics. Two major research lines are pursued by the MBPCG: 1. The search for prostate cancer oncogenes and tumor suppressor genes. Microarray and next generation sequencing technologies are used to analyze differential expression, epigenetic changes as well as gene copy number alterations. Special emphasis is placed on non-coding RNAs (ncRNA), especially on microRNAs (miRNA). The clinical significance of these genes is evaluated with the aid of population based tissue microarrays and their function is analyzed in cellular models – the ultimate goal being the development of novel diagnostic and therapeutic tools. 2. Characterization of the AR signaling pathway in the tumorigenesis of prostate cancer. Over 60 years after the discovery of the importance of androgens in prostate cancer, there is still no curative treatment for castration-resistant prostate cancer. MBPCG is exploring strategies to therapeutically interfere with androgen signaling. The androgen receptor (AR) itself is a potent therapy target, but downstream target genes or AR co-factors might also provide means for therapeutic intervention. A new ARoverexpression model for prostate cancer has been developed by the group to identify these genes and co-factors, and to study their functional significance. Several such protein-coding genes and miRNAs have already been identified with the help of the model. Currently their significance is under investigation. One known downstream target gene of AR signaling is the oncogenic transcription factor ERG (and some of its family members) which is recurrently fused with TMPRSS2 (or other androgenregulated genes) in prostate cancer. The significance of the fusion driven overexpression is also under investigation.

Our main focus is on prostate cancer (PrCa) genetics and we are also working on the genetic bases of hereditary breast cancer. There is genetic predisposition to aggressive cancer and cancer specific deaths. Therefore genetic markers should be found that could be used as to identify individuals at elevated risk. Currently in PrCa, however there are no reliable means to accurately distinguish risk for life-threatening, aggressive PrCa from the overwhelming majority of indolent cases. Therefore we aim to 1) identify new risk factors and explain their functionality in prostate carcinogenesis. This would have diagnostic applicability, especially for more aggressive disease, at an early, curable stage, and 2) develop tools for prognostic purposes, i.e. prognostic biomarkers, which are urgently needed in clinical practice. We combine traditional genetic analyses with functional genomics and array-based applications. Multiple methods are used in order to identify genes that are mutated, differentially expressed or copy-number altered. Main collaborators CPCG (International Consortium for Prostate Cancer Genetics); PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome); ProspeR (Prostate cancer: profiling and evaluation of ncRNA); TPCRP (Translational Prostate Cancer Research Program); Professor Anssi Auvinen and Professor Hannu Oja, Departments of Epidemiology and Biostatistics at the Tampere School of Public Health and Dr. Joan Bailey-Wilson, National Institutes of Health (USA). Funding The Academy of Finland, Finnish Cancer Organizations, the Sigrid Juselius Foundation, the Reino Lahtikari Foundation, the National Institutes of Health (USA), Medical Research Fund of Tampere University Hospital (EVO). Personnel Group Leader: Post-doctoral Fellow: PhD Students:

Undergraduate Students: Laboratory staff:

Other staff:

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Main collaborators EU-FP7-ProspeR consortium; EU-FP7-PRO-NEST; Professor Robert Vessella (University of Washington, USA); Dr. Steven Bova ( Johns Hopkins University, USA); Professor Jorma Palvimo (University of Kuopio, Finland); Professor Olli Jänne (University of Helsinki, Finland); Dr. Matti Nykter and Dr. Harri Lähdesmäki (Tampere University of Technology, Finland); TPCRP (Translational Prostate Cancer Research Program) Funding

Professor Johanna Schleutker, PhD

The Academy of Finland, the European Commission, the Medical Research Fund of Tampere University Hospital, the Sigrid Jusélius Foundation, the Cancer Society of Finland, the Reino Lahtikari Foundation, OrionPharma Ltd

Tiina Wahlfors, PhD

Personnel

Sanna Pakkanen, MD Sanna Siltanen, MSc Kirsi Kuusiato, MSc Riikka Nurminen, MSc Daniel Fischer, MSc Virpi Laitinen, MSc

Group Leader: Post-doctoral Fellows:

Aleksandra Bebel Ekaterina Slitikova

PhD Students:

Linda Enroth, Technician Riitta Vaalavuo, Research Nurse Riina Liikala, Technician Clinical contributors: Professor Teuvo Tammela, MD, PhD Mika Matikainen, MD, PhD

Institute of Medical Technology

Annual Report 2010

Professor Tapio Visakorpi, MD, PhD Merja Helenius, PhD Kati Porkka, PhD Outi Saramäki, PhD Leena Latonen, PhD Kati Waltering, PhD Hanna Rauhala, PhD

Undergraduate Students:

Laboratory staff:

Visa Manni Erinn-Lee Ogg, placement student Simone McSeveney, placement student Mariitta Vakkuri, technician Päivi Martikainen, technician

Sanni Jalava, MSc Anchit Khanna, MSc Saara Lehmusvaara, MSc Katri Leinonen, MSc Mauro Scaravilli, MSc Hanna Suikki, MSc Kirsi Tuppurainen, MSc Alfonso Urbanucci, MSc Erik Veskimäe, MD Teemu Tolonen, MD Rasa Sabaliauskaite, ERASMUS student

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Cell Interactions Our main interest is in the role of ADAM metalloproteinase-disintegrins in intercellular communication. ADAMs are the principal ectodomain sheddases which can activate growth factors, cytokines, and other mediators from their membrane-bound precursors as well as down-regulate receptors and adhesion proteins. ADAMs can also mediate cell adhesion. We address the molecular mechanism of physiological ADAM regulation and the altered ADAM regulation in pathological conditions, particularly in vascular disease and cancer. We have identified the Src-homology-3 (SH3) proteins interacting with human ADAMs as candidate regulators of their activity and targeting. ADAMs appear to have characteristic SH3-binding profiles with some specific and some common interactions. These studies have been carried out in collaboration with Prof. Saksela’s laboratory (University of Helsinki). Further characterization of select ADAM-SH3 interactions in cells is ongoing.

Cellular Biology

We are particularly interested in human ADAM15, implicated both in physiological and pathological processes through ectodomain shedding and cell-cell interactions. We have shown that the alternative ADAM15 exons are differentially used in human tissues, giving rise to mRNA variants encoding ADAM15 isoforms with cytosolic tails carrying different complements of SH3-interaction motifs. The alternative ADAM15 tails show differential SH3-binding, suggesting that ADAM15 function is regulated at the level of differential alternative exon use. The alternative ADAM15 exon use is misregulated in human cancers. The tumors are distributed into a few different clusters according to their ADAM15 mRNA variant profiles, suggesting that different variant patterns reflect specific defects in the splice control mechanism. Misregulated ADAM15 splicing appears to be associated with clinical traits such as EGFR status and tumor angiogenesis. We investigated the misregulation of ADAMs in the vascular diseases in collaboration with the Tampere University Hospital and the AtheroRemo Consortium. Several ADAMs have been implicated in atherosclerosis and sudden cardiac death. Altogether, our recent results provide novel insights into ADAM regulation and accentuate the pro- and diagnostic potential of ADAM15 in vascular disease and cancer. Main collaborators Professor Terho Lehtimäki, Tampere University Hospital, Finland; Professor Kalle Saksela, Haartman Institute, University of Helsinki, Finland; Professor Anthony Turner, IMCB, University of Leeds, UK; Professor Markku Pelto-Huikko, University of Tampere Medical School, Finland; Dr. Hannu Haapasalo, Dept. of Pathology, Tampere University Hospital, Finland. Funding The Medical Research Fund of Tampere University Hospital Personnel Group Leader: Post-doctoral Fellow: PhD Student: Undergraduate Student:

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Annual Report 2010

Ari-Pekka Huovila, PhD Iivari Kleino, PhD Rebekka Ortiz, MD Paula Koskela

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Biochemistry of Cell Signaling The mammalian p21-activated kinases (PAKs) 1-3 act as downstream effectors of the small GTPases Cdc42 and Rac1 and play important roles in the regulation of the actin cytoskeleton morphology, the transduction of signals controlling gene expression, and the execution of programmed cell death. The roles of PAKs in these pivotal cellular processes have directed significant attention to understanding how the activity of these serine/threonine kinases is controlled. The N-terminal regulatory domain of the various PAK family members contains several potential SH3-domain binding PxxP-motifs, some of which have been found to play important roles in the activation and cellular localization of the kinases. We have screened a proteome-wide phage-display library to identify all SH3-domains binding to PAK1-3. From this screen we have identified several new PAK-interacting proteins, among which are POSH2 and all members of the vinexin protein family. We are currently studying the roles of these interactions in different PAK functions. Main collaborators

Professor Kalle Saksela, University of Helsinki, Finland; Professor Ole Nørregaard Jensen, University of Southern Denmark, Denmark Funding

The Academy of Finland, the Medical Research Fund of Tampere University Hospital. Personnel Group Leader:

Herma Renkema, PhD

Post-doctoral Fellow:

Marita Hiipakka, PhD

PhD Students:

Hanna Polari, MSc Satu Kärkkäinen, MSc

Laboratory staff:

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Mitochondria FinMIT’s research groups aim to derive new knowledge about the structure, function and regulation of mitochondria, and use this to develop novel strategies for therapy of mitochondrial disorders.

Kristina Lehtinen, Technician

Institute of Medical Technology

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Mitochondrial Gene Expression and Disease

Mitochondrial Biogenesis in Health and Disease

Defects in the mitochondrial OXPHOS system cause a wide variety of human diseases, ranging from fatal infantile disorders to neurodegenerative pathologies of old age, also including a substantial proportion of cases of common conditions, such as deafness, diabetes, epilepsy, and cardiomyopathy. We are engaged in a long-term effort to identify at the molecular level the pathological mechanisms associated with these disorders, aiming to use this knowledge to design effective therapeutic interventions.

Research in our lab is centered on studies of mitochondrial biogenesis in health and disease. Our focus is on mitochondrial DNA transactions, which represent the first phase of the mitochondrial life cycle. We use a multi-disciplinary strategy to study mtDNA replication and transcription, and their regulation by nuclear-mitochondrial communication, including biochemical, molecular genetic, structural and computational approaches to understand enzyme and protein function in both human and Drosophila systems. We translate our findings into biological models of mitochondrial function and dysfunction in fly cell culture and in animals. In collaboration with Professor Howy Jacobs, we are also exploring the effects of mtDNA haplotype on mtDNA copy number, organismal fitness and longevity.

Our effort is divided into three directions: 1. Basic studies of the mitochondrial genetic system: we are studying mitochondrial DNA (mtDNA) replication using a combination of 2D agarose gel electrophoresis, LM-PCR and electron microscopy, combined with regulated expression of key mtDNA-binding proteins. We have elaborated a new model for metazoan mtDNA replication involving a transient RNA lagging strand. In human heart we have found evidence for a distinct type of mtDNA replication involving recombination, which can be experimentally induced by several different transgenic manipulations. 2. Analysis of mitochondrial disease models in Drosophila: we are using a combination of transcriptomics, proteomics, transgenetics and classical genetics to profile gene expression and identify target tissues, compensatory pathways and genetic and environmental suppressors of Drosophila mutants that model OXPHOS disease in humans, focusing initially on the tko mutant, which has a general defect in mitochondrial protein synthesis. 3. Development of a novel gene-therapy approach to mitochondrial disorders: we are testing the potential of the alternative oxidase (AOX) from Ciona intestinalis, as well as single-subunit NADH dehydrogenases, to act as a by-pass of the cytochrome segment of the OXPHOS system under conditions where it is deficient or malfunctioning. In both human cells and Drosophila, AOX renders mitochondrial respiration insensitive to inhibitors such as cyanide or antimycin, diminishes the production of toxic oxygen radicals, and complements the phenotypes of some specific OXPHOS disease mutations. Preliminary findings also indicate intriguing effects on lifespan.

We currently have open positions for professional researchers and postdoctoral fellows in both the protein and mtDNA projects funded by the U.S. National Institutes of Health, the Academy of Finland and the FinMit Centre of Excellence in Research on Mitochondrial Disease and Ageing. Applicants for these positions, and interested Finnish M.Sc. and Ph.D. candidates are welcome to submit a statement of research interests and qualifications, curriculum vitae and letters of reference to [email protected] uta.fi. Opportunities area available to work both at the University of Tampere, Finland and Michigan State University, U.S.A. Personnel Group Leader: PhD Student: Laboratory staff:

Professor Laurie Kaguni Tiina Riihimäki Jokela Merja, Laboratory technician

Main collaborators Group leader Ian Holt, MRC-Mitochondrial Biology, Cambridge, UK; Dr. Pierre Rustin, INSERM, Hôpital Debré, Paris, France; Dr. Kevin O’Dell, University of Glasgow, UK; Professor Dongchon Kang, Kyushu University, Fukuoka, Japan; Professor Nils-Göran Larsson and Aleksandra Trifunovic, Karolinska Institute, Stockholm, Sweden. Funding The Academy of Finland (FinMIT Centre of Excellence), the European Research Council, the Sigrid Juselius Foundation, the Tampere University Hospital Medical Research Fund, EMBO, EU Personnel Group Leader: Post-doctoral Fellows:

Shanjun Chen, PhD Giuseppe Cannino, PhD Eric Dufour, PhD Atsushi Fukuoh, PhD Priit Jöers, PhD Alberto Sanz, PhD Jacek Lenart, PhD Suvi Vartiainen, PhD

PhD Students:

Anne Hyvärinen, MSc Kia Kemppainen, MSc Esko Kemppainen, MSc

Undergraduate Students:

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Academy Professor Howy Jacobs, PhD Laboratory staff:

Other staff:

Tea Tuomela, Technician Päivi Lillsunde, Technician Bettina Hutz, Technician Marja Pirinen, Technician Essi Kiviranta, Technician Marika Vähä-Jaakkola, Technician Rhoda Stefanatos, Research Assistant Päivi Manninen, Project Manager

Matti Lakanmaa Marie Chalons Lucile Boyer Angela Wilson, Erasmus-student Kirsty Allan Anna Popplestone Akbar Zeb

Institute of Medical Technology

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Mitochondrial Gerontology and Age-related Diseases Group Ageing is a universal process of degeneration that impairs the capacity of an individual to cope with stress. We aim to understand how this ageing occurs in order to delay this process and prolong healthy lifespan. Recently it has emerged that mitochondria play a critical role in the regulation of ageing. We utilize the power of Drosophila genetics in combination with various cellular, biochemical and physiological approaches to manipulate mitochondrial function and increase maximum lifespan. This approach should prolong healthy lifespan and delay ageing-related diseases (cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, Alzheimer’s disease). Main collaborators Professor Christiaan Leeuwenburgh, University of Florida (USA), Dr. Daniel Fernandez-Ayala, Pablo Olavide University (Spain), Professor Howy Jacobs, University of Tampere (Finland), Professor Reinald Pamplona, University of Lleida (Spain) and Dr. Ricardo Gredilla, Complutense University of Madrid (Spain) Funding The European Research Council, the Medical Research Fund of Tampere University Hospital (EVO) Personnel Group Leader: Undergraduate Student: Other staff:

Alberto Sanz, PhD Mohan Aravind Kumar Essi Kiviranta, Research assistant

Mitochondrial DNA Maintenance Group FinMIT Centre of Excellence, Tampere, Finland Institute for Genetic and Metabolic Disease, Radboud University Nijmegen, the Netherlands Apart from a few well characterized proteins, little is known about the molecular mechanisms involved in mitochondrial DNA (mtDNA) organization, replication and repair. As part of ongoing research, several years ago we identified a new mitochondrial protein called Twinkle. It was shown that mutations in the gene for Twinkle, in families of several ethnic origins including one Finnish family, are associated with a late onset disorder: autosomal dominant Progressive External Opthalmoplegia (adPEO). In addition, the mitochondrial DNA polymerase POLG has been recognized as an adPEO disease gene. AdPEO is characterized by the accumulation of mtDNA deletions in the brain and skeletal muscle, and is clinically identified by ophthalmoparesis and exercise intolerance, but can also show other variable phenotypes. Other adPEO genes remain to be identified. Our research pursues a better understanding of the role of Twinkle in human disease, identification of new components of the mtDNA maintenance machinery, and to better understanding of the processes of mtDNA maintenance in both health and disease. More specifically, the research aims are to: 1. Elucidate the enzymatic and cellular effects of Twinkle adPEO mutations and to establish the functions of Twinkle in mtDNA metabolism and organization 2. Systematically identify new proteins involved in mtDNA maintenance using various approaches, including biochemical isolation of mitochondrial DNA/protein complexes 3. Functionally characterize newly identified proteins involved in mtDNA maintenance 4. Understand the dynamics of mitochondrial gene segregation at the cell biology level. Main collaborators Professor Anu Wartiovaara, Biomedicum Helsinki, Finland; Group leader Ian Holt, MRC-Mitochondrial Biology, Cambridge, UK; Professor Howy Jacobs, University of Tampere, Finland; Professor Eric Verdin, UCSF, USA. Funding The Academy of Finland, EVO, IMT, the Netherlands Organization for Scientific Research (NWO) Personnel Group Leader: Post-doctoral Fellows: PhD Students:

Hans Spelbrink, PhD (Nijmegen, Tampere) Lucia Valente, PhD (Nijmegen) Joachim M. Gerhold, PhD (Nijmegen) Nina Rajala, PhD student (Tampere) Fenna Hensen, PhD student (Nijmegen) Sirin Cansiz, PhD student (Nijmegen)

Undergraduate Students:

Alexey Klymov, MSc. student (Nijmegen) Mai Nguyen, BSc. student (Nijmegen)

Laboratory staff:

Merja Jokela, technician (Tampere) Outi Kurronen, technician (Tampere) Helga van Rennes, technician (Nijmegen)

Home page: http://www.ncmd.nl/page/309/mitochondrial-dna-maintenance.htm

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Genetic Immunology It takes several days or even weeks for our immune system to develop a specific immune response. Nevertheless, most of us stay alive, and often healthy, thanks to an elaborate system of rapidly activated innate immune defenses. Work on insects and other invertebrates that lack an acquired immune response has played an important role for the progress of this field. Our research group has developed Drosophila as a useful model system to study innate immunity. The insight that immune reactions in insects are closely related to the human innate immune defense has led to a rapidly growing interest in this model in recent years. In addition, insect immunity is of intrinsic interest because insects are vectors for serious human disease, and because insect pathogens are increasingly used to control agricultural pests. The immune response in Drosophila includes both humoral and cellular components. The humoral response is manifest in the production of potent antimicrobial peptides. The molecular mechanisms of this response have been investigated intensely and are now reasonably well understood. By contrast, much less is known about the cellular part of this immune system, which is capable of relatively sophisticated functions such as the recognition, encapsulation and killing of parasites, and the phagocytosis of bacteria.

Molecular immunology

The aim of the molecular immunology groups is to reveal the basic mechanisms that regulate immune response and to use this information to develop novel therapeutic or preventive strategies.

Over the years, our laboratory in Umeå, Sweden, has engaged in fruitful collaboration with the laboratory of Prof. Mika Rämet in Tampere. A FiDiPro grant from the Academy of Finland made it possible for us to set up a laboratory at IMT, and thereby intensifying the collaboration with the Rämet laboratory as well as with Prof. Olli Silvennoinen and others at IMT. During 2010, we recruited more co-workers and set up new projects. Our work is conducted in close collaboration with the recently set-up Biocenter Finland -funded Drosophila core facility (http://cofa.uta.fi/drosophila_index.php). Main collaborators Professor Istvan Ando, Biological Research Center, Hungarian Academy of Science, Szeged, Hungary; Professor Ronald van Rij, Radboud University, Nijmegen, the Netherlands; Professor Andrew G. Clark, Cornell University, USA; Professor Todd Schlenke, Emory University, USA; Professor Jay Evans, USDA-ARS, USA; Professor Thomas Kieselbach, Department of Chemistry, Umeå University, Sweden; Professor Gunnar Wingsle, Umeå Plant Science Centre, Sweden; Professor Ruth Palmer, Department of Molecular Biology, Umeå University, Sweden; Professor Mika Rämet, Institute of Medical Technology, University of Tampere, Finland. Funding The Academy of Finland, the Swedish Research Council, the Swedish Cancer Society. Personnel Group Leader: Post-doctoral Fellow: PhD Students: Undergraduate Students: Laboratory staff:

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Professor Dan Hultmark, Ph.D. Anni Kleino, Ph.D. Ines Anderl, Dipl. Biol. Volker von Gernler, Dipl. Biol. Sina Saari Otto Mäkelä Tuula Myllymäki

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Immunoregulation

Experimental Immunology

Our group investigates the regulative mechanisms of immune cells with special deference to on the role of proprotein convertases (PC). PCs cleave and convert immature proproteins into functional end products. We have previously shown that the expression of a PC family member furin is highly regulated in immune cells and its expression in T cells is critical for the maintenance of peripheral immune tolerance. Moreover, our results indicate that furin is essential for Th1 type cell-mediated immunity and adequate development of immune cells.

Most important physiological mechanisms are conserved in evolution, and therefore it is possible to use genetically tractable model organisms such as the fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio) to study genetic diseases, and also complex diseases like cancer, cardiovascular diseases or diabetes. Our research group uses fruit flies and zebrafish in order to investigate the immune response mechanisms. Flies have a highly effective innate immune response. In contrast to mammals, Drosophila has no adaptive i.e. antibody-mediated immunity, which makes it a valid model for studying the pattern recognition receptors and signaling pathways of innate immunity. The conservation between the most important immunity signaling pathways in Drosophila (Toll, Imd and JAK/STAT pathways) and the human pathways mediating inflammation (IL-1/TLR, TNF and JAK/STAT) is especially striking. We have used Drosophila as a model to discover novel classes of gene products that are important in combatting pathogens mainly by using an in-house developed RNA interference (RNAi) -based in vitro screening method in Drosophila S2 cells (Rämet et al. (2002) Nature). This screening method has been utilized on genome-wide scale to study the functional significance of gene products for numerous cell based functions using our unique collection of dsRNAs covering the entire Drosophila genome. In recent years we have used this collection successfully to identify new proteins necessary for: 1.) recognition and phagocytosis of bacteria (Rämet et al., 2002 Nature; Kocks et al., 2005 Cell; Ulvila et al., 2011 J Leukoc Biol); 2.) the RNAi phenomenon itself (Ulvila et al., 2006 JBC) 3.) NF-kappaB signaling (Kleino et al., 2005 EMBO Journal; Kleino et al., 2008 J Immunol, Valanne et al., 2010 J Immunol) and 4.) JAK/STAT signaling (Kallio et al., 2010 FASEB J). In addition to the Drosophila model, we have established a state-of-the-art zebrafish facility in order to carry out large-scale genetic screens in zebrafish. The zebrafish has recently emerged as a powerful model for infectious diseases and immune function. As a vertebrate, it is evolutionarily relatively close to humans and has a fully developed immune system. Compared with other vertebrate models zebrafish are small, fast-growing, inexpensive and easy to manipulate genetically. These characteristics make it possible to carry out large-scale mutagenesis screens or to create extensive infection models using the zebrafish model. Mycobacterium marinum, a close relative of M. tuberculosis, is used widely as a model to study M. tuberculosis pathogenesis. It causes a granulomatous, tuberculosislike disease in zebrafish and leads to both innate and adaptive immune responses. We study the genetic networks underlying the mechanisms of innate and adaptive immune responses in mycobacterial infections by forward genetic analysis in the zebrafish model. Secondly, we are developing a mycobacterial vaccination model in the zebrafish system. See: Biocenter Finland Funded Core Facilities on page 11.

In the future we shall continue to explore the molecular mechanisms of furin in T cells and its role as a regulator of immune homeostasis. We are also interested in how PC family members may contribute to the pathogenesis of immune-mediated diseases, such as autoimmunity or allergy. In addition, we want to understand how PCs regulate hematopoiesis and contribute to the host defense against diverse pathogens. The Immunoregulation Group was founded in 2009 and currently consists of three postdoctoral fellows, two technicians and one PhD student. We have expertise in the methodology that is essential for analyzing immune cell function including primary cell cultures, flow cytometry, cytokine measurements and T regulatory cell suppression assays. Main collaborators Scientific Director John O’Shea (NIAMS/NIH, USA), Group Leader John Creemers (University of Leuven, the Netherlands), Professor Mika Rämet (University of Tampere, Finland), Group Leader, Head of Proteomics Garry Corthals (University of Turku, Finland), Docent Panu Kovanen (University of Helsinki, Finland) Funding The European Union, the Academy of Finland, the Medical Research Fund of Tampere University Hospital (EVO), the Sigrid Juselius Foundation, the Emil Aaltonen Foundation. Personnel Group Leader: Post-doctoral Fellow:

Researchers:

Laboratory staff:

Main collaborators

Marko Pesu, PhD Kati Pulkkinen, PhD Hannu Turpeinen, PhD Zsuzsanna Ortutay, PhD

Professor Dan Hultmark, Umeå University, Sweden & Institute of Medical Technology, University of Tampere, Finland, Professor Christine Kocks, Harvard Medical School, USA, Professor Ylva Engström, Stockholm University, Sweden, Professor Mikko Hallman, University of Oulu, Finland, Professor Olli Silvennoinen, Institute of Medical Technology, University of Tampere, Finland.

Zuzet Martinez Cordova, MSc Anna Oksanen, BSc

Funding

Sanna Hämäläinen, laboratory technician Annemari Latvala, laboratory technician

The Academy of Finland, the Sigrid Juselius Foundation, the Competitive Research Funding of Pirkanmaa Hospital District (EVO), the Foundation for Pediatric Research, the Emil Aaltonen Foundation, the Tampere Tuberculosis Foundation Personnel Group Leader: Post-doctoral Fellows:

PhD Students:

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Institute of Medical Technology

Annual Report 2010

Professor Mika Rämet MD, PhD Susanna Valanne, PhD Mataleena Parikka, DDS, PhD Jinghuan Wang, PhD Johanna Ulvila, PhD (University of Oulu) Anni Kleino, MSc Jenni Kallio, MSc Henna Myllymäki, MSc Leena-Maija Vanha-aho, MSc Sanna-Kaisa Harjula, MSc Marika Lahtinen, MSc

Undergraduate Students:

Laboratory staff:

Kaisa Oksanen Milka Vuoksio Meri Kaustio Anni Järvinen Elina Pajula Nick Halfpenny Leena Mäkinen Matilda Martikainen Tuula Myllymäki

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Molecular Immunology - Cytokine Receptor Signaling Cytokines regulate the growth and differentiation of hematopoietic cells through the activation of JAK tyrosine kinases and STAT transcription factors. Deregulated activation of the JAK/STAT pathway has been implicated in human diseases, particularly in cancer, hematological disorders, allergies and autoimmune diseases. An understanding of the mechanisms of JAK/STAT activation at the molecular and atomic level will provide the molecular basis for designing intervention strategies and methodologies for the screening and development of therapeutic compounds. Our research projects focus on structure/function analysis and posttranslational modifications of the JAK/STAT pathway. Aberrant activation of JAK kinases, e.g. by point mutations or translocations, lead to cellular transformation and cancer. Point mutations in the JH2 (pseudokinase) domain of JAK2 cause Polycytemia Vera and other myeloproliferative diseases. Our laboratory has conducted pioneering work in characterizing the function of JH2 in regulation of JAK kinases, and the disease causing mutations in JAK2 and JAK3 localized in the inhibitory region identified previously in our studies. Present works defines the molecular mechanism of JH2 mediated JAK regulation during cytokine receptor activation, and aim at characterizing JAKs at the structural level. In collaboration with Professor Mika Rämet We are also investigating novel regulators of JAK-STAT signaling identified in a genome wide screen. We are investigating the molecular mechanisms of STAT mediated gene regulation. STAT6 plays a decisive role in allergic responses, and we adopted a combined biochemical and structural approach to analyze the composition, structure and function of the STAT6 enhanceosome. Through a direct proteome approach we have identified transcriptional coregulators for STAT6. The first of the regulators identified, Tudor-SN (p100/SND1), was found to participate in several aspects of cellular RNA metabolism, and to function both as an interaction surface for transcription factors and in pre-mRNA processing via the so-called Tudor domain (TD). In collaboration with Dr J. Liu we have crystallized the TD of Tudor-SN allowing detailed analysis of the TD function. Recently in collaboration with P. Botzhkov we also identified a novel function of Tudor-SN in regulation of apoptosis. Current studies focus on gaining an in-depth understanding of the Tudor-SN function as an RNA-binding protein and regulator of gene expression using Next-Generation Sequencing technologies and Tudor-SN knockout mouse model.

Affiliated groups

The affiliated groups have focused their research on cell physiology and molecular pathogenic mechanisms of certain diseases, such as coeliac disease and cancer.

Main collaborators Professor S. Hubbard, NYU Medical School, USA; Professor O.N. Jensen, University of Southern Denmark, Denmark; Professor H. Alenius, Finnish Institute of Occupational Health, Finland and EU FP6 Marie Curie RTN on Cytokine Receptors in Disease; Dr. J. Yang, Tianjin Medical University, China Funding The Academy of Finland, the Sigrid Juselius Foundation, the Pirkanmaa Hospital District, the Finnish Funding Agency for Technology and Innovation (TEKES) Personnel Group Leader: Post-doctoral Fellows: PhD Students:

Undergraduate Student: Laboratory staff: Other staff:

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Professor Olli Silvennoinen, MD, PhD Daniela Ungureanu PhD Juha Saarikettu, PhD Juha Grönholm, Bachelor of Medicine Tekele Fashe, DVM, MSc   Yashavanthi Niranjan, MSc Jie Shao, visiting PhD student Tuija Pekkala, BSc Paula Kosonen, Technician Merja Lehtinen, Technician Visiting professor Jie Yang, MD, PhD Pia Isomäki, MD, PhD Samuli Rouninoja, MD, PhD Xianzhi Zhang, PhD

Institute of Medical Technology

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Coeliac Disease Study Group

Tissue Biology Group

Coeliac disease (CD) is intolerance to dietary gluten present in wheat, rye and barley and belongs to the most common food related life-long disorders in Europe and the United States. A typical feature for CD, in addition to the small intestinal mucosal changes, is gluten dependent serum IgA class autoantibodies which are widely used in clinical practice in selecting patients to undergo diagnostic intestinal biopsy. Although the target of these antibodies is known to be transglutaminase 2 (TG2), the role of these autoantibodies in CD pathogenesis is far from clear with the generally accepted view of CD as a T-cell-mediated disorder. Today, the only effective treatment for CD is a life-long gluten-free diet, where wheat, rye and barley are excluded. As adhering to a strict gluten-free diet is burdensome, new treatment options are needed.

The research in the Tissue Biology Group is focused on cellular pH homeostasis regulated by carbonic anhydrase (CA) enzymes.

The aim of our study group is to ascertain how large a proportion of the entire Finnish population suffers from gluten intolerance and thus need to permanently exlude gluten from their daily diet in order to sustain health and general well-being and to prevent the protean associated diseases and complications of CD. We also hope to develop more efficient, simple and non-invasive diagnostic tools, both serology-based and genetic, that enable the identification of the vulnerable gluten-sensitive population subgroup who already benefit from life-long gluten-free diet in the early phase of the disease process. Our group also aims to study the mechanism behind gluten-toxicity and the role of disease-specific autoantibodies in pathogenesis. Our goal is also to eliminate the coeliac-toxic/ immunogenic fractions present in wheat, rye and barley in order to develop new coeliac-safe foods and carry out preclinical and clinical studies of novel treatment options. Main collaborators The “TRACKS” Consortium, the “TRANSCOM” Consortium (Professor M. Griffin, coordinator); the ELVIRA “MANGLIN” Consortium (Professors J. Kere, P. Männistö and P. Salovaara); Docent Päivi Saavalainen, University of Helsinki; Docent J. Partanen and J. Mättö, the Finnish Red Cross; Professor H. Hyöty, University of Tampere; Ikihyvä project (MD, PhD L. Luostarinen); National Public Health Institute (Professors. A. Reunanen and P. Knekt); Professor M. Hadjivassiliou, University of Sheffield, UK; MD PhD A. Stanescu-Popp, Romania; Prof. H. Wieser, Deutsche Forschungsanstalt für Lebensmittelchemie, Garching, Germany; Professor C. Khosla, University of Stanford, USA, Professor B. Jabri, University of Chigaco, Chigaco, USA, Dr D. Leffler, Harvard Medical School, USA; professor P. Daugherty and Dr J. Ballew, University of California-Santa Barbara, USA; professor JR Bilbao, University of Basque Country, Barakaldo, Spain, Professor C. Esposito, University of Salerno, Italy, Dr R. Anderson, The Walter & Eliza Hall Institute of Medical Research (WEHI), Melbourne, Australia; Industrial collaborators: Anibiotech Oy, ChemoCentryx Ltd., Alvine Pharmaceuticals Ltd. Funding The European Commission, the Academy of Finland, TEKES, the Competitive Research Funding of Pirkanmaa Hospital District, the Paediatric Research Foundation, the Sigrid Juselius Foundation, the Research Foundation of the Finnish Coeliac Society, the Finnish Foundation of Gastroenterological Research, the Finnish Cultural Foundation, the Finnish Medical Society Duodecim Personnel

Group Leader: Principal Investigators:

PhD Students:

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Professor Markku Mäki, MD, PhD

Undergraduate Students:

Docent Katri Kaukinen, MD, PhD Docent Pekka Collin, MD, PhD Docent Katri Lindfors, PhD Associate professor Ilma Korponay-Szabo, MD, PhD Sergio Caja, PhD Marja-Leena Lähdeaho, MD, PhD Kalle Kurppa, MD, PhD (10/2010) Essi Myrsky, MSc/PhD (05/2010) Satumarja Stenman, MSc Tiina Rauhavirta, MSc Cristina Nadalutti, MSc Laura Airaksinen, MSc Suvi Kalliokoski, MSc Outi Koskinen, MD, PhD (05/2010) Anniina Ukkola, MD Anitta Vilppula, MD Anitta Ruuskanen, MD

Institute of Medical Technology

Visiting students: Laboratory staff:

Other staff:

Annual Report 2010

Carbonic anhydrases are enzymes that catalyze the reversible hydration of carbon dioxide according to the following reaction: CO2 + H2O ↔ HCO3- + H+. The main function of this protein family is to regulate pH homeostasis in different organisms, including eukaryotes, bacteria and archaea. The alpha-CA gene family present in mammals includes 13 enzymatically active members. Additional gene families are also expressed in various species other than human. These include beta-, gamma-, epsilon-, and zeta-CAs. One major line in our research is the investigation of the distribution and functional significance of cancer-associated CA isozymes (CA II, VII, IX and XII) in normal and pathological tissues. In these investigations, we utilize CA knockout mouse models, which are excellent tools for physiological studies. In 2010 our group was involved in the European Union DeZnIT Consortium, which aimed to design and produce novel inhibitor molecules against zinc enzymes including different CAs. One major task of our group was to produce different CA isozymes as recombinant proteins for characterization and drug design studies. In 2010 we also established a knockout mouse model of CA VI deficiency. CA VI is the only secretory isozyme of the alpha-CA gene family. The enzyme is present in saliva and milk, and its physiological functions have been remained unclear. In a recent article, we characterized CA VI deficient mice and described several interesting alterations in gene expression levels, which may help to understand the role of CA VI. In the past year we also reported and characterized the first beta-CA in Drosophila melanogaster and currently aim to isolate the same enzyme from pathogenic organisms, such as Anopheles mosquito. Our group has also extended out research to three novel members of the alpha-CA family. Carbonic anhydrase-related proteins (CARPs) are structurally quite similar to classical CAs. The main exception is the lack of the critical histidine residues in the active site cavity, which are important for CA catalytic activity. Therefore CARPs are catalytically inactive, but they have other roles, especially in the central nervous system. In human and mouse cerebellum, CARP VIII protein is linked to movement coordination. In 2010 we reported the distribution of all CARPs in mouse tissues and phylogenetic analysis of CARPs in a number of different species. The results led us to investigate further the role of CARPs, and we selected zebrafish as a model organism. These studies are underway in our laboratory and the first results on CARP VIII knockdown zebrafish will be submitted for publication in near future. Main collaborators Professor William S. Sly, Saint Louis University School of Medicine, USA; Professors Silvia and Jaromir Pastorek, Institute of Virology, Slovak Academy of Sciences, Slovak Republic; Professor Claudiu Supuran, Università degli Studi di Firenze, Italy; Professor Onni Niemelä, EP Central Hospital and University of Tampere, Finland; Dr. Hannu Haapasalo, Laboratory Centre, Tampere University Hospital, Finland; Dr. Vesa Hytönen, Institute of Medical Technology, University of Tampere, Finland. Funding The European Union Grant (DeZnIT), the Academy of Finland, the Sigrid Juselius Foundation, the Medical Research Fund of Tampere University Hospital.

Satu Korpimäki Sampsa Kinos Olli Lauronen Ida Lahtinen Pilvi Paarlahti Asif Rasheed Jaakko Salminiemi Juha Taavela Boglarka Toth Jennifer Cullighan

Personnel

Kaija Laurila, MSc, Head of Laboratory Jorma Kulmala, Technician Mervi Himanka, Tecnician Soili Peltomäki, Technician Anne Heimonen, Technician

Undergraduate Students:

Kaija Kaskela, Project secretary Marja-Terttu Oksanen, Research nurse

Group Leader:

Post-doctoral Fellows: PhD Students:

Laboratory staff:

Professor Seppo Parkkila, MD, PhD Peiwen Pan, PhD Ashok Aspatwar, PhD Piritta Hynninen, MD Joonas Haapasalo, MD Martti Tolvanen, Phil. lic. Fatemeh Ahmad, MSc Heini Kallio, MSc Leo Syrjänen Anna Lappalainen Anna-Kaisa Harju Aulikki Lehmus, Technician Marianne Kuuslahti, Technician

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The Biotechnology Program

Master’s Degree Program in Bioinformatics

Since 2001 the Biotechnology Program at the Institute of Medical Technology has been offering interdisciplinary BSc and MSc degrees. The fundamental objective of the Program is to educate a new generation of young scientists with outstanding theoretical knowledge and state-of-the-art research skills to harness the potential of biosciences for the development of wellbeing. Special emphasis is placed on the biomedical branch of biotechnology, which can be considered one of the core areas of the research conducted in IMT. The Program has increasingly intensive collaboration with Tampere University of Technology, and vital international ERASMUS exchange of students and teacher mobility with the University of Glasgow in Scotland and the National University of Ireland in Galway. In addition it has educational contacts with the national biotechnology industry and is engaged with various departments at the University of Tampere in interdisciplinary teaching. Teaching is mostly provided by the Program staff with the help of other IMT academic personnel and educational partners. Annual intake is 25-30 students. The majority of the funding comes from the University budget and complementary funding has been received from the BioneXt Project by the City of Tampere.

The Master’s Degree Program in Bioinformatics is co-operative joint operation between our Institute and the Department of Information Technology at the University of Turku. The program was launched in 2006, and was the first international master’s degree program in bioinformatics in Finland. This program aims at imparting interdisciplinary knowledge of bioinformatics, and the joint expertise of the participating institutions has been essential in arranging the courses. All teaching is given in English, and the students learn to work together with associates from different countries and different scientific backgrounds. Instruction takes advantage of modern technology, for example web courses, video lectures, and video conferencing, in addition to traditional contact teaching.

After completing the BSc degree, the students enter advanced studies where they have a choice of the four fields of specialization: 1) Molecular biology 2) Bioinformatics 3) Cell and tissue technology 4) Biobusiness In the first nine years of the Program nearly 60 students graduated and the great majority of them have found placements academic research, industrial R&D and marketing or teaching. Several students have continued their postgraduate studies abroad prestigious research institutions, e.g. EMBL in Heidelberg, Germany, and the University of Cambridge, UK. The rapid development and success of the Program is based on the devoted staff and well-motivated students. The Program provides a firm foundation for further development and continuing success in the future, due to the closer and more intensive educational collaboration with the Tampere University of Technology.

Students are required to have a bachelor degree or equivalent in biosciences or information technology, or in other relevant method sciences, such as statistics. The studies encompass different aspects of bioinformatics, computer science, information technology and biosciences, including biochemistry, genetics, and molecular biology. After preliminary courses which provide background information when needed, the students take the courses together. At the end of their studies, students are able combine knowledge of information technology and biosciences to accomplish complex analysis and data mining tasks of biological data. The program has been running successfully. Student enrolment has been organized annually with an intake of 15 students per university. . Teaching staff: Professor Mauno Vihinen, PhD Csaba Ortutay, PhD, Docent in Bioinformatics Senior Research Associate Martti Tolvanen, Ph.Lic.

Present staff of the Biotechnology Program: Professor Markku Kulomaa PhD Professor Anne Kallioniemi, MD, PhD University Lecturer Olli Jaakkola, PhD Senior Research Associate Ari Huovila, PhD Senior Research Associate Jarkko Valjakka, PhD Senior Research Associate Martti Tolvanen, MSc Lecturer Helena Torkkeli, PhD, MBA Laboratory techinican Janette Hinkka Coordinator Marjatta Viilo, MSocSc Administrator Riitta Aallos, MA Study Secretary Mira Pihlström, MSocSc Master’s theses at the Master’s Degree Program in Bioinformatics

Master’s theses at the Biotechnology Program Niskanen Ville - Selvitys nonkliinisen tutkimuspalvelukokonaisuuden luomisesta Tampereen alueelle (31.12.2010)

Tirkkonen Laura - The effects of vibration loading on adipose stem cell viability, proliferation and osteogenic differentiation (10.6.2010)

Kotha Sreevani Analysis of missense mutations in adenosine deaminase using Pathogenic-Or-Not-Pipeline (PON-P) (20.12.2010)

Kuivanen Juuso - Engineering of Saccharomyces cerevisiae for carboxylic acid production (31.11.2010) 

Kukkola Saija - HLA-DQ2-geenien promoottorialueiden metylaatio keliakiassa (3.6.2010)

Nair Preethy Codon usage bias of the overlapping genes in microbial genomes (3.11.2010)

Airaksinen Laura - Kaura ja keliakia - kauraperäisten molekyylien hyödyt ja haitat in vitro (29.11.2010) 

Kukkola Saara - The effect of androgen receptor overexpression on its recruitment to the regulatory regions of PSA and TMPRSS2 genes (7.5.2010)

Teku Gabriel Transcriptional regulation of bidirectional promoters: role of NF-Y (1.4.2010)

Kärkkäinen Pauliina - Nucleolar proteomics in acute leukaemia (24.11.2010) Mustalahti Eero - Expression and purification of endoplasmic reticulum-targeted hydrophobin fusions in Nicotiana benthamiana and Trichoderma reesei (28.10.2010) Patrikainen Mimmi - HNF1B-geenin karakterisointi suomalaisissa eturauhassyöpäperheissä (12.8.2010)

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Institute of Medical Technology

Laurila Kirsti - In silico analysis of point mutation effects on transcription factor binding and protein subcellular localization (26.4.2010)

Dai Xiaofeng A joint finite mixture model for clustering genes from beta, Gaussian and Bernoulli distributed data (7.1.2010)

Kotipelto Tapio - Steroidihormonien molekulaarinen tunnistus proteiineilla (26.2.2010) Mäntymaa Anne - The effects of hypoxic condition on the chondrogenic differentiation of adipose stem cells (12.2.2010)

Annual Report 2010

39

Tampere Graduate Program in Biomedicine and Biotechnology (TGPBB)

Dissertations 2010 in TGPBB

The first graduate school at the Institute of Medical Technology (IMT) was established in 1995. After a series of organizational changes, the Tampere Graduate School in Biomedicine and Biotechnology (TGSBB) was officially founded in 2003 (name changed in 2010 to its present form: TGPBB). Today TGPBB consists of students from IMT, the Medical School, Regea Institute for Regenerative Medicine and Tampere University of Technology (TUT). The board of TGPBB consists of representatives from IMT, Regea Institute for Regenerative Medicine and the Faculty of Medicine as well as a PhD student member.

Kati Pulkkinen HIV-1 Nef protein and the Nef-associating kinase PAK2 in cell signaling http://acta.uta.fi/teos.php?id=11295 Supervised by Kalle Saksela 5.2.2010

The mission of TGPBB is to provide excellent quality graduate training in biosciences, especially in the disciplines of molecular biology, biomedicine, biotechnology, and bioinformatics. TGPBB aims to equip graduate students with high standard academic skills that allow them to pursue successful careers, e.g. in science, medicine or biotechnology. TGPBB is genuinely committed to the goals set by the Ministry of Education for graduate training. These include active development of professional research careers, improved planning of dissertation work, clarification and strengthening of the responsibilities of supervisors, enhancement of national and international collaboration, and finally, the generation of high quality PhD dissertations within a 4-year training period. A wide variety of seminars and courses is offered and students are also actively encouraged to participate in other local, national and international training courses, for example those organized by the Finnish Graduate School Network in Life Sciences (FinBioNet). An important part of TGPBB is the financial support that the School provides for students to attend training courses and scientific meetings. The Director and the Board of TGPBB are responsible for the successful implementation of the mission of the school and are in charge of student selection and the development of a high quality curriculum. Currently, there are 34 research groups with 49 professor or docent level dissertation supervisors enrolled in TGPBB and approximately 80 registered students are working towards a doctoral degree in TGSBB affiliated laboratories. In 2010, TGPBB had a total of 20 graduate student positions funded by the Ministry of Education to support full-time graduate research. Additional information on TGPBB can be found at http://www.uta.fi/ibt/tgpbb Director of TGPBB Professor Johanna Schleutker

TGPBB board (since 1.3.2009-) Professor Anne Kallioniemi, IMT Professor Hans Spelbrink, IMT Professor Pekka Karhunen, Faculty of Medicine Professor Mikko Hurme, Faculty of Medicine Academy Research Fellow Heli Skottman, Regea Graduate student Alfonso Urbanucci, IMT

Institute of Medical Technology

Määttä Juha Structural and Functional Characterization of Engineered Avidin Proteins http://acta.uta.fi/teos.php?id=11334 Supervised by Markku Kulomaa and Vesa Hytönen 11.6.2010 Anni Kleino The Imd pathway-mediated immune response in Drosophila http://acta.uta.fi/teos.php?id=11340 Supervised by Mika Rämet 23.6.2010 Janita Thusberg Molecular effects of missense mutations - Bioinformatics analysis of genetic defects http://acta.uta.fi/teos.php?id=11342 Supervised by Mauno Vihinen 2.7.2010

Coordinator of TGPBB Henna Mattila, PhD

40

Sofia Khan Mutational effects on protein structures: Knowledge gained from databases, predictions and protein models http://acta.uta.fi/teos.php?id=11297 Supervised by Mauno Vihinen 8.2.2010

Annual Report 2010

Kati Waltering Androgen receptor signaling pathway in prostate cancer http://acta.uta.fi/teos.php?id=11350 Supervised by Tapio Visakorpi 10.9.2010 Sanna Pakkanen Profiling of High-risk Prostate Cancer Families in Finland http://acta.uta.fi/teos.php?id=11363 Supervised by Teuvo Tammela and Johanna Schleutker 12.11.2010 Anne Hyvärinen Functional analysis of the MTERF protein family in cultured human cells http://acta.uta.fi/teos.php?id=11373 Supervised by Howard T. Jacobs 20.11.2010 Katri Köninki HER-2 positive breast cancer - molecular and epidemiological studies http://acta.uta.fi/teos.php?id=11390 Supervised by Jorma Isola 2.12.2010 Riina Kuuselo MED29 possesses a complex role in pancreatic cancer http://acta.uta.fi/teos.php?id-11394 Supervised by Anne Kallioniemi and Ritva Karhu 17.12.2010

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Bioinformatics

Cancer Biology

Kohonen-Corish MR, Al-Aama JY, Auerbach AD, Axton M, Barash CI, Bernstein I, Béroud C, Burn J, Cunningham F, Cutting GR, den Dunnen JT, Greenblatt MS, Kaput J, Katz M, Lindblom A, Macrae F, Maglott D, Möslein G, Povey S, Ramesar R, Richards S, Seminara D, Sobrido MJ, Tavtigian S, Taylor G, Vihinen M, Winship I, Cotton RG, How to catch all those mutations--the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010. Hum Mutat 2010 ;31(12)1374-81

Tuominen VJ, Ruotoistenmäki S, Viitanen A, Jumppanen M, Isola J ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Breast Cancer Res 2010 ;12(4)R56

Laurila K, Vihinen M PROlocalizer: integrated web service for protein subcellular localization prediction. Amino Acids 2010 ; Lanzi G, Ferrari S, Vihinen M, Caraffi S, Kutukculer N, Schiaffonati L, Plebani A, Notarangelo LD, Fra AM, Giliani S Different molecular behavior of CD40 mutants causing hyperIgM syndrome. Blood 2010 ;116(26)5867-74 Khan S, Vihinen M Performance of protein stability predictors. Hum Mutat 2010 ;31(6)675-84 Howard HJ, Horaitis O, Cotton RG, Vihinen M, Dalgleish R, Robinson P, Brookes AJ, Axton M, Hoffmann R, Tuffery-Giraud S The Human Variome Project (HVP) 2009 Forum “Towards Establishing Standards”. Hum Mutat 2010 ;31(3)366-7 Ortutay, C., Olatubosun, A., Parkkila, S., Vihinen, M., and Tolvanen, M. An evolutionary analysis of insect carbonic anhydrases. (2010) Adv. Med. Biol., Vol. 7, 145-168.

Protein Dynamics Huhti L, Blazevic V, Nurminen K, Koho T, Hytönen VP, Vesikari T A comparison of methods for purification and concentration of norovirus GII-4 capsid virus-like particles. Arch Virol 2010 ;155(11)1855-8 Syrjänen L, Tolvanen M, Hilvo M, Olatubosun A, Innocenti A, Scozzafava A, Leppiniemi J, Niederhauser B, Hytönen VP, Gorr TA, Parkkila S, Supuran CT Characterization of the first beta-class carbonic anhydrase from an arthropod (Drosophila melanogaster) and phylogenetic analysis of beta-class carbonic anhydrases in invertebrates. BMC Biochem 2010 ;1128

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Institute of Medical Technology

Saarilahti K, Bono P, Kajanti M, Bäck L, Leivo I, Joensuu T, Isola J, Mäkitie AA Phase II prospective trial of gefitinib given concurrently with cisplatin and radiotherapy in patients with locally advanced head and neck cancer. J Otolaryngol Head Neck Surg 2010 ;39(3)269-76 Köninki K, Barok M, Tanner M, Staff S, Pitkänen J, Hemmilä P, Ilvesaro J, Isola J Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells. Cancer Lett 2010 ;294(2)211-9 Parkkila S, Lasota J, Fletcher JA, Ou WB, Kivelä AJ, Nuorva K, Parkkila AK, Ollikainen J, Sly WS, Waheed A, Pastorekova S, Pastorek J, Isola J, Miettinen M Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Mod Pathol 2010 ;23(5)743-50 Staff S, Isola J, Jumppanen M, Tanner M Aurora-A gene is frequently amplified in basal-like breast cancer. Oncol Rep 2010 ;23(2)307-12 Joensuu G, Joensuu T, Nokisalmi P, Reddy C, Isola J, Ruutu M, Kouri M, Kupelian PA, Collan J, Pesonen S, Hemminki A A phase I/II trial of gefitinib given concurrently with radiotherapy in patients with nonmetastatic prostate cancer. Int J Radiat Oncol Biol Phys 2010 ;78(1)42-9 Tuominen VJ, Isola J Linking whole-slide microscope images with DICOM by using JPEG2000 interactive protocol. J Digit Imaging 2010 ;23(4)454-62

Cancer Genomics Kallioniemi A DNA copy number analysis on tissue microarrays. Methods Mol Biol 2010 ;664127-34 Wolf M, Korja M, Karhu R, Edgren H, Kilpinen S, Ojala K, Mousses S, Kallioniemi A, Haapasalo H Array-based gene expression, CGH and tissue data defines a 12q24 gain in neuroblastic tumors with prognostic implication. BMC Cancer 2010 ;10181

Annual Report 2010

Alarmo EL, Kallioniemi A Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis? Endocr Relat Cancer 2010 ;17(2)R123-39 Kuuselo R, Simon R, Karhu R, Tennstedt P, Marx AH, Izbicki JR, Yekebas E, Sauter G, Kallioniemi A 19q13 amplification is associated with high grade and stage in pancreatic cancer. Genes Chromosomes Cancer 2010 ;49(6)569-75 Ketolainen JM, Alarmo EL, Tuominen VJ, Kallioniemi A Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4. Breast Cancer Res Treat 2010 ;124(2)377-86

Genetic Predisposition to Cancer Nurminen R, Wahlfors T, Tammela TL, Schleutker J Identification of an aggressive prostate cancer predisposing variant at 11q13. Int J Cancer 2010 ; Christensen GB, Baffoe-Bonnie AB, George A, Powell I, Bailey-Wilson JE, Carpten JD, Giles GG, Hopper JL, Severi G, English DR, Foulkes WD, Maehle L, Moller P, Eeles R, Easton D, Badzioch MD, Whittemore AS, Oakley-Girvan I, Hsieh CL, Dimitrov L, Xu J, Stanford JL, Johanneson B, Deutsch K, McIntosh L, Ostrander EA, Wiley KE, Isaacs SD, Walsh PC, Isaacs WB, Thibodeau SN, McDonnell SK, Hebbring S, Schaid DJ, Lange EM, Cooney KA, Tammela TL, Schleutker J, Paiss T, Maier C, Grönberg H, Wiklund F, Emanuelsson M, Farnham JM, Cannon-Albright LA, Camp NJ, Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics using novel sumLINK and sumLOD analyses. Prostate 2010 ;70(7)735-44

Molecular Biology of Prostate Cancer (MBPCG) Gu L, Zhu XH, Visakorpi T, Alanen K, Mirtti T, Edmonston TB, Nevalainen MT Activating mutation (V617F) in the tyrosine kinase JAK2 is absent in locally-confined or castration-resistant prostate cancer. Anal Cell Pathol (Amst) 2010 ;33(2)55-9 Waltering KK, Porkka KP, Jalava SE, Urbanucci A, Kohonen PJ, Latonen LM, Kallioniemi OP, Jenster G, Visakorpi T Androgen regulation of micro-RNAs in prostate cancer. Prostate 2010 ;

Pittman AM, Naranjo S, Jalava SE, Twiss P, Ma Y, Olver B, Lloyd A, Vijayakrishnan J, Qureshi M, Broderick P, van Wezel T, Morreau H, Tuupanen S, Aaltonen LA, Alonso ME, Manzanares M, Gavilán A, Visakorpi T, Gómez-Skarmeta JL, Houlston RS Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H. PLoS Genet 2010 ;6(9) Erkkilä T, Lehmusvaara S, Ruusuvuori P, Visakorpi T, Shmulevich I, Lähdesmäki H Probabilistic analysis of gene expression measurements from heterogeneous tissues. Bioinformatics 2010 ;26(20)2571-7 Leinonen KA, Tolonen TT, Bracken H, Stenman UH, Tammela TL, Saramäki OR, Visakorpi T Association of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancer. Clin Cancer Res 2010 ;16(10)2845-51 Suikki HE, Kujala PM, Tammela TL, van Weerden WM, Vessella RL, Visakorpi T Genetic alterations and changes in expression of histone demethylases in prostate cancer. Prostate 2010 ;70(8)889-98 Rauhala HE, Jalava SE, Isotalo J, Bracken H, Lehmusvaara S, Tammela TL, Oja H, Visakorpi T miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer. Int J Cancer 2010 ;127(6)1363-72

Biochemistry of Cell Signaling Kärkkäinen S, van der Linden M, Renkema GH POSH2 is a RING finger E3 ligase with Rac1 binding activity through a partial CRIB domain. FEBS Lett 2010 ;584(18)3867-72

Mitochondrial Gene Expression and Disease Hyvärinen AK, Kumanto MK, Marjavaara SK, Jacobs HT Effects on mitochondrial transcription of manipulating mTERF protein levels in cultured human HEK293 cells. BMC Mol Biol 2010 ;1172 Chua YL, Dufour E, Dassa EP, Rustin P, Jacobs HT, Taylor CT, Hagen T Stabilization of hypoxia-inducible factor-1alpha protein in hypoxia occurs independently of mitochondrial reactive oxygen species production. J Biol Chem 2010 ;285(41)31277-84

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Jiménez-Menéndez N, Fernández-Millán P, Rubio-Cosials A, Arnan C, Montoya J, Jacobs HT, Bernadó P, Coll M, Usón I, Solà M Human mitochondrial mTERF wraps around DNA through a left-handed superhelical tandem repeat. Nat Struct Mol Biol 2010 ;17(7)891-3 Pohjoismäki JL, Goffart S, Taylor RW, Turnbull DM, Suomalainen A, Jacobs HT, Karhunen PJ Developmental and pathological changes in the human cardiac muscle mitochondrial DNA organization, replication and copy number. PLoS One 2010 ;5(5)e10426 Sanz A, Fernández-Ayala DJ, Stefanatos RK, Jacobs HT Mitochondrial ROS production correlates with, but does not directly regulate lifespan in Drosophila. Aging (Albany NY) 2010 ;2(4)220-3 Sanz A, Soikkeli M, Portero-Otín M, Wilson A, Kemppainen E, McIlroy G, Ellilä S, Kemppainen KK, Tuomela T, Lakanmaa M, Kiviranta E, Stefanatos R, Dufour E, Hutz B, Naudí A, Jové M, Zeb A, Vartiainen S, Matsuno-Yagi A, Yagi T, Rustin P, Pamplona R, Jacobs HT Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci U S A 2010 ;107(20)9105-10 Pohjoismäki JL, Holmes JB, Wood SR, Yang MY, Yasukawa T, Reyes A, Bailey LJ, Cluett TJ, Goffart S, Willcox S, Rigby RE, Jackson AP, Spelbrink JN, Griffith JD, Crouch RJ, Jacobs HT, Holt IJ Mammalian mitochondrial DNA replication intermediates are essentially duplex but contain extensive tracts of RNA/DNA hybrid. J Mol Biol 2010 ;397(5)1144-55 Fernández-Ayala DJ, Chen S, Kemppainen E, O’Dell KM, Jacobs HT Gene expression in a Drosophila model of mitochondrial disease. PLoS One 2010 ;5(1)e8549

Mitochondrial Biogenesis in Health and Disease Oliveira MT, Kaguni LS Functional roles of the N- and C-terminal regions of the human mitochondrial single-stranded DNA-binding protein. PLoS One 2010 ;5(10)e15379 Matsushima Y, Goto Y, Kaguni LS Mitochondrial Lon protease regulates mitochondrial DNA copy

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Institute of Medical Technology

number and transcription by selective degradation of mitochondrial transcription factor A (TFAM). Proc Natl Acad Sci U S A 2010 ;107(43)18410-5 Makowska-Grzyska MM, Ziebarth TD, Kaguni LS Physical analysis of recombinant forms of the human mitochondrial DNA helicase. Methods 2010 ;51(4)411-5 Ziebarth TD, Gonzalez-Soltero R, Makowska-Grzyska MM, Núñez-Ramírez R, Carazo JM, Kaguni LS Dynamic effects of cofactors and DNA on the oligomeric state of human mitochondrial DNA helicase. J Biol Chem 2010 ;285(19)14639-47 Dallmann HG, Fackelmayer OJ, Tomer G, Chen J, WiktorBecker A, Ferrara T, Pope C, Oliveira MT, Burgers PM, Kaguni LS, McHenry CS Parallel multiplicative target screening against divergent bacterial replicases: identification of specific inhibitors with broad spectrum potential. Biochemistry 2010 ;49(11)2551-62 Palin EJ, Lesonen A, Farr CL, Euro L, Suomalainen A, Kaguni LS Functional analysis of H. sapiens DNA polymerase gamma spacer mutation W748S with and without common variant E1143G. Biochim Biophys Acta 2010 ;1802(6)545-51 Oliveira MT, Garesse R, Kaguni LS Animal models of mitochondrial DNA transactions in disease and ageing. Exp Gerontol 2010 ;45(7-8)489-502

Mitochondrial Gerontology and Age-related Diseases Hiona A, Sanz A, Kujoth GC, Pamplona R, Seo AY, Hofer T, Someya S, Miyakawa T, Nakayama C, Samhan-Arias AK, Servais S, Barger JL, Portero-Otín M, Tanokura M, Prolla TA, Leeuwenburgh C Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One 2010 ;5(7)e11468 Sanz A, Fernández-Ayala DJ, Stefanatos RK, Jacobs HT Mitochondrial ROS production correlates with, but does not directly regulate lifespan in Drosophila. Aging (Albany NY) 2010 ;2(4)220-3 Sanz A, Soikkeli M, Portero-Otín M, Wilson A, Kemppainen

Annual Report 2010

E, McIlroy G, Ellilä S, Kemppainen KK, Tuomela T, Lakanmaa M, Kiviranta E, Stefanatos R, Dufour E, Hutz B, Naudí A, Jové M, Zeb A, Vartiainen S, Matsuno-Yagi A, Yagi T, Rustin P, Pamplona R, Jacobs HT Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci U S A 2010 ;107(20)9105-10 Sanz A, Stefanatos R, McIlroy G Production of reactive oxygen species by the mitochondrial electron transport chain in Drosophila melanogaster. J Bioenerg Biomembr 2010 ;42(2)135-42

Molecular Biology-Mitochondrial DNA maintenance Pohjoismäki JL, Holmes JB, Wood SR, Yang MY, Yasukawa T, Reyes A, Bailey LJ, Cluett TJ, Goffart S, Willcox S, Rigby RE, Jackson AP, Spelbrink JN, Griffith JD, Crouch RJ, Jacobs HT, Holt IJ Mammalian mitochondrial DNA replication intermediates are essentially duplex but contain extensive tracts of RNA/DNA hybrid. J Mol Biol 2010 ;397(5)1144-55 Spelbrink JN Functional organization of mammalian mitochondrial DNA in nucleoids: history, recent developments, and future challenges. IUBMB Life 2010 ;62(1)19-32

Genetic Immunology

Werren JH, Richards S, Desjardins CA, Niehuis O, Gadau J, Colbourne JK, , Werren JH, Richards S, Desjardins CA, Niehuis O, Gadau J, Colbourne JK, Beukeboom LW, Desplan C, Elsik CG, Grimmelikhuijzen CJ, Kitts P, Lynch JA, Murphy T, Oliveira DC, Smith CD, van de Zande L, Worley KC, Zdobnov EM, Aerts M, Albert S, Anaya VH, Anzola JM, Barchuk AR, Behura SK, Bera AN, Berenbaum MR, Bertossa RC, Bitondi MM, Bordenstein SR, Bork P, Bornberg-Bauer E, Brunain M, Cazzamali G, Chaboub L, Chacko J, Chavez D, Childers CP, Choi JH, Clark ME, Claudianos C, Clinton RA, Cree AG, Cristino AS, Dang PM, Darby AC, de Graaf DC, Devreese B, Dinh HH, Edwards R, Elango N, Elhaik E, Ermolaeva O, Evans JD, Foret S, Fowler GR, Gerlach D, Gibson JD, Gilbert DG, Graur D, Gründer S, Hagen DE, Han Y, Hauser F, Hultmark D, Hunter HC, Hurst GD, Jhangian SN, Jiang H, Johnson RM, Jones AK, Junier T, Kadowaki T, Kamping A, Kapustin Y, Kechavarzi B, Kim J, Kim J, Kiryutin B, Koevoets T, Kovar CL, Kriventseva EV, Kucharski R, Lee H, Lee SL, Lees K, Lewis LR, Loehlin DW, Logsdon JM, Lopez JA, Lozado RJ, Maglott D, Maleszka R, Mayampurath A, Mazur DJ, McClure MA, Moore AD, Morgan MB, Muller J, Munoz-Torres MC, Muzny DM, Nazareth LV, Neupert S, Nguyen NB, Nunes FM, Oakeshott JG, Okwuonu GO, Pannebakker BA, Pejaver VR, Peng Z, Pratt SC, Predel R, Pu LL, Ranson H, Raychoudhury R, Rechtsteiner A, Reese JT, Reid JG, Riddle M, Robertson HM, Romero-Severson J, Rosenberg M, Sackton TB, Sattelle DB, Schlüns H, Schmitt T, Schneider M, Schüler A, Schurko AM, Shuker DM, Simões ZL, Sinha S, Smith Z, Solovyev V, Souvorov A, Springauf A, Stafflinger E, Stage DE, Stanke M, Tanaka Y, Telschow A, Trent C, Vattathil S, Verhulst EC, Viljakainen L, Wanner KW, Waterhouse RM, Whitfield JB, Wilkes TE, Williamson M, Willis JH, Wolschin F, Wyder S, Yamada T, Yi SV, Zecher CN, Zhang L, Gibbs RA Functional and evolutionary insights from the genomes of three parasitoid Nasonia species. Science 2010 ;327(5963)343-8

Immunoregulation

Pokrzywa M, Dacklin I, Vestling M, Hultmark D, Lundgren E, Cantera R Pesu M Uptake of aggregating transthyretin by fat body in a Drosophila [T-helper cells--bandleaders of immune response]. model for TTR-associated amyloidosis. Duodecim 2010 ;126(18)2179-87 PLoS One 2010 ;5(12)e14343 Valanne S, Myllymäki H, Kallio J, Schmid MR, Kleino A, Murumägi A, Airaksinen L, Kotipelto T, Kaustio M, Ulvila J, Esfahani SS, Engström Y, Silvennoinen O, Hultmark D, Parikka M, Rämet M Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-kappaB signaling. J Immunol 2010 ;184(11)6188-98

Experimental Immunology Kaikkonen S, Räsänen S, Rämet M & Vesikari T. Aichi virus infection in children with acute gastroenteritis in Finland. Epidemiology and Infection 2010, 138:1166-71. Valtonen TM, Kleino A, Rämet M & Rantala MJ. Starvation reveals maintenance cost of humoral immunity. Evolutionary Biology 2010, 37:49-57.

Ulvila J, Hultmark D, Rämet M RNA silencing in the antiviral innate immune defence--role of DEAD-box RNA helicases. Ulvila J, Hultmark D & Rämet M. Scand J Immunol 2010 ;71(3)146-58 RNA silencing in the antiviral innate immune defense--Role of

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DEAD-box RNA helicases. Scandinavian Journal of Immunology 2010.; 71:146-158. Wang JH, Valanne S & Rämet M. Drosophila as a model for antiviral immunity. World Journal of Biological Chemistry 2010;1(5):151-159. Hyvärinen J, Parikka M, Sormunen R, Rämet M, Tryggvason K, Kivirikko KI, Myllyharju J, Koivunen P Deficiency of a transmembrane prolyl 4-hydroxylase in the zebrafish leads to basement membrane defects and compromised kidney function. J Biol Chem 2010 ;285(53)42023-32 Rämet M, Hallman M Surfactant proteins and respiratory syncytial virus. J Pediatr 2010 ;157(5)866; author reply 866-7 Kallio J, Myllymäki H, Grönholm J, Armstrong M, Vanha-aho LM, Mäkinen L, Silvennoinen O, Valanne S, Rämet M Eye transformer is a negative regulator of Drosophila JAK/ STAT signaling. FASEB J 2010 ;24(11)4467-79 Grönholm J, Ungureanu D, Vanhatupa S, Rämet M, Silvennoinen O Sumoylation of Drosophila transcription factor STAT92E. J Innate Immun 2010 ;2(6)618-24 Löfgren J, Marttila R, Renko M, Rämet M, Hallman M Toll-like receptor 4 Asp299Gly polymorphism in respiratory syncytial virus epidemics. Pediatr Pulmonol 2010 ;45(7)687-92 Valanne S, Myllymäki H, Kallio J, Schmid MR, Kleino A, Murumägi A, Airaksinen L, Kotipelto T, Kaustio M, Ulvila J, Esfahani SS, Engström Y, Silvennoinen O, Hultmark D, Parikka M, Rämet M Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-kappaB signaling. J Immunol 2010 ;184(11)6188-98

Molecular Immunology Gao X, Ge L, Shao J, Su C, Zhao H, Saarikettu J, Yao X, Yao Z, Silvennoinen O, Yang J Tudor-SN interacts with and co-localizes with G3BP in stress granules under stress conditions. FEBS Lett 2010 ;584(16)3525-32 Kallio J, Myllymäki H, Grönholm J, Armstrong M, Vanha-aho

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LM, Mäkinen L, Silvennoinen O, Valanne S, Rämet M Eye transformer is a negative regulator of Drosophila JAK/ STAT signaling. FASEB J 2010 ;24(11)4467-79

Millan S, Murray L, Metzger MH, Gasparin M, Bravi E, Mäki M, The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann Med 2010 ;42(8)587-95

Grönholm J, Ungureanu D, Vanhatupa S, Rämet M, Silvennoinen O Sumoylation of Drosophila transcription factor STAT92E. J Innate Immun 2010 ;2(6)618-24

Kaukinen K, Lindfors K, Collin P, Koskinen O, Mäki M Coeliac disease--a diagnostic and therapeutic challenge. Clin Chem Lab Med 2010 ;48(9)1205-16

Saarikettu J, Ovod V, Vuoksio M, Grönholm J, Yang J, Silvennoinen O Monoclonal antibodies against human Tudor-SN. Hybridoma (Larchmt) 2010 ;29(3)231-6

Lindfors K, Mäki M, Kaukinen K Transglutaminase 2-targeted autoantibodies in celiac disease: Pathogenetic players in addition to diagnostic tools? Autoimmun Rev 2010 ;9(11)744-9

Valanne S, Myllymäki H, Kallio J, Schmid MR, Kleino A, Murumägi A, Airaksinen L, Kotipelto T, Kaustio M, Ulvila J, Esfahani SS, Engström Y, Silvennoinen O, Hultmark D, Parikka M, Rämet M Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-kappaB signaling. J Immunol 2010 ;184(11)6188-98

Ruuskanen A, Kaukinen K, Collin P, Huhtala H, Valve R, Mäki M, Luostarinen L Positive serum antigliadin antibodies without celiac disease in the elderly population: does it matter? Scand J Gastroenterol 2010 ;45(10)1197-202

Coeliac Disease Study Salmi TT, Collin P, Reunala T, Mäki M, Kaukinen K. Diagnostic methods beyond conventional histology in coeliac disease diagnosis.Dig Liver Dis 2010;42:28-32. Stenman SM, Lindfors K, Venäläinen JI, Hautala A, Männistö PT, Garcia-Horsman JA, Kaukovirta-Norja A, Auriola S, Mauriala T, Mäki M, Kaukinen K. Degradation of coeliac disease-inducing rye secalin by germinating cereal enzymes: diminishing toxic effects in intestinal epithelial cells. Clin Exp Immunol 2010;161:242-9. Sundman L, Saarialho-Kere U, Vendelin J, Lindfors K, Assadi G, Kaukinen K, Westerholm-Ormio M, Savilahti E, Mäki M, Alenius H, D’Amato M, Pulkkinen V, Kere J, Saavalainen P.Neuropeptide S receptor 1 expression in the intestine and skin--putative role in peptide hormone secretion. Neurogastroenterol Motil. 2010;22:79-87. Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, de Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT; Finnish Celiac Disease Study Group, Joosten LA, Saavalainen P, van Heel DA, Catassi C, Netea MG, Wijmenga C. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection.Am J Hum Genet 2010;86:970-7.

Mustalahti K, Catassi C, Reunanen A, Fabiani E, Heier M, Mc-

Annual Report 2010

Koskinen O, Lindfors K, Collin P, Peräaho M, Laurila K, Woolley N, Partanen J, Mäki M, Kaukinen K Intestinal transglutaminase 2 specific antibody deposits in nonresponsive coeliac disease. Dig Liver Dis 2010 ;42(10)692-7 Kaukinen K, Collin P, Mäki M [Celiac disease--a diagnostic and therapeutic challenge]. Duodecim 2010 ;126(3)245-54 Kurppa K, Ashorn M, Iltanen S, Koskinen LL, Saavalainen P, Koskinen O, Mäki M, Kaukinen K Celiac disease without villous atrophy in children: a prospective study. J Pediatr 2010 ;157(3)373-80, 380.e1 Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adány R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernández-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Mäki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Núñez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 2010 ;42(4)295-302

Caja S, Myrsky E, Korponay-Szabo IR, Nadalutti C, Sulic AM, Lavric M, Sblattero D, Marzari R, Collighan R, Mongeot A, Griffin M, Mäki M, Kaukinen K, Lindfors K Inhibition of transglutaminase 2 enzymatic activity ameliorates the anti-angiogenic effects of coeliac disease autoantibodies. Scand J Gastroenterol 2010 ;45(4)421-7 Collin P, Mäki M, Kaukinen K Revival of gliadin antibodies in the diagnostic work-up of celiac disease. J Clin Gastroenterol 2010 ;44(3)159-60 Kurppa K, Collin P, Sievänen H, Huhtala H, Mäki M, Kaukinen K Gastrointestinal symptoms, quality of life and bone mineral density in mild enteropathic coeliac disease: a prospective clinical trial. Scand J Gastroenterol 2010 ;45(3)305-14 Dahlbom I, Korponay-Szabó IR, Kovács JB, Szalai Z, Mäki M, Hansson T Prediction of clinical and mucosal severity of coeliac disease and dermatitis herpetiformis by quantification of IgA/IgG serum antibodies to tissue transglutaminase. J Pediatr Gastroenterol Nutr 2010 ;50(2)140-6 Koskinen O, Collin P, Lindfors K, Laurila K, Mäki M, Kaukinen K Usefulness of small-bowel mucosal transglutaminase-2 specific autoantibody deposits in the diagnosis and follow-up of celiac disease. J Clin Gastroenterol 2010 ;44(7)483-8

Tissue Biology Hallerdei J, Scheibe RJ, Parkkila S, Waheed A, Sly WS, Gros G, Wetzel P, Endeward V T tubules and surface membranes provide equally effective pathways of carbonic anhydrase-facilitated lactic acid transport in skeletal muscle. PLoS One 2010 ;5(12)e15137 Pan PW, Käyrä K, Leinonen J, Nissinen M, Parkkila S, Rajaniemi H Gene expression profiling in the submandibular gland, stomach, and duodenum of CAVI-deficient mice. Transgenic Res 2010 ; Pan PW, Waheed A, Sly WS, Parkkila S Carbonic anhydrases in the mouse harderian gland. J Mol Histol 2010 ;41(6)411-7 Aspatwar A, Tolvanen ME, Ortutay C, Parkkila S Carbonic anhydrase related protein VIII and its role in neurodegeneration and cancer. Curr Pharm Des 2010 ;16(29)3264-76

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BMC Cancer 2010 ;10104 Di Fiore A, Truppo E, Supuran CT, Alterio V, Dathan N, Bootorabi F, Parkkila S, Monti SM, De Simone G Crystal structure of the C183S/C217S mutant of human CA VII in complex with acetazolamide. Bioorg Med Chem Lett 2010 ;20(17)5023-6 Syrjänen L, Tolvanen M, Hilvo M, Olatubosun A, Innocenti A, Scozzafava A, Leppiniemi J, Niederhauser B, Hytönen VP, Gorr TA, Parkkila S, Supuran CT Characterization of the first beta-class carbonic anhydrase from an arthropod (Drosophila melanogaster) and phylogenetic analysis of beta-class carbonic anhydrases in invertebrates. BMC Biochem 2010 ;1128

Saari S, Hilvo M, Pan P, Gros G, Hanke N, Waheed A, Sly WS, Parkkila S The most recently discovered carbonic anhydrase, CA XV, is expressed in the thick ascending limb of Henle and in the collecting ducts of mouse kidney. PLoS One 2010 ;5(3)e9624 Baranauskiene. L, Hilvo M, Matuliene. J, Golovenko D, Manakova E, Dudutiene. V, Michailoviene. V, Torresan J, Jachno J, Parkkila S, Maresca A, Supuran CT, Gražulis S, Matulis D Inhibition and binding studies of carbonic anhydrase isozymes I, II and IX with benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulphonamides. J Enzyme Inhib Med Chem 2010 ;25(6)863-70

Kallio H, Hilvo M, Rodriguez A, Lappalainen EH, Lappalainen AM, Parkkila S Global transcriptional response to carbonic anhydrase IX defi- Parkkila S, Lasota J, Fletcher JA, Ou WB, Kivelä AJ, Nuorva K, ciency in the mouse stomach. Parkkila AK, Ollikainen J, Sly WS, Waheed A, Pastorekova S, BMC Genomics 2010 ;11397 Pastorek J, Isola J, Miettinen M Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Oksala N, Levula M, Pelto-Huikko M, Kytömäki L, Soini JT, Mod Pathol 2010 ;23(5)743-50 Salenius J, Kähönen M, Karhunen PJ, Laaksonen R, Parkkila S, Lehtimäki T Carbonic anhydrases II and XII are up-regulated in osteoclast- Agborsangaya C, Toriola AT, Grankvist K, Surcel HM, Holl K, like cells in advanced human atherosclerotic plaques-Tampere Parkkila S, Tuohimaa P, Lukanova A, Lehtinen M Vascular Study. The effects of storage time and sampling season on the stability Ann Med 2010 ;42(5)360-70 of serum 25-hydroxy vitamin D and androstenedione. Nutr Cancer 2010 ;62(1)51-7 Bootorabi F, Jänis J, Smith E, Waheed A, Kukkurainen S, Hytönen V, Valjakka J, Supuran CT, Vullo D, Sly WS, Parkkila S Analysis of a shortened form of human carbonic anhydrase VII expressed in vitro compared to the full-length enzyme. Biochimie 2010 ;92(8)1072-80

Temperini C, Innocenti A, Scozzafava A, Parkkila S, Supuran CT The coumarin-binding site in carbonic anhydrase accommodates structurally diverse inhibitors: the antiepileptic lacosamide as an example and lead molecule for novel classes of carbonic anhydrase inhibitors. Nordfors K, Haapasalo J, Korja M, Niemelä A, Laine J, Parkkila J Med Chem 2010 ;53(2)850-4 AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila S, Haapasalo H The tumour-associated carbonic anhydrases CA II, CA IX and Agborsangaya CB, Surcel HM, Toriola AT, Pukkala E, Parkkila CA XII in a group of medulloblastomas and supratentorial prim- S, Tuohimaa P, Lukanova A, Lehtinen M itive neuroectodermal tumours: an association of CA IX with Serum 25-hydroxyvitamin D at pregnancy and risk of breast poor prognosis. cancer in a prospective study. BMC Cancer 2010 ;10148 Eur J Cancer 2010 ;46(3)467-70

Tampere Graduate Program of Biomedicine and Biotechnology TGPBB is a joint graduate program with participants from the Institute of Biomedical Technology and the Medical School, University of Tampere and the Departments of Signal Processing, Biomedical Engineering, and Automation Science, Tampere University of Technology. TGPBB focuses on multidisciplinary research training in molecular biology, biomedicine, biotechnology, bioinformatics, cell biology and systems biology. Currently, there are 45 research groups enrolled in TGPBB and approximately 80 registered students are working towards a doctoral degree in TGPBB affiliated laboratories. TGPBB has 20 graduate student positions funded by the Ministry of Education and Culture to support full-time graduate research. In 2010, 13 students completed their doctorates, and in 2008-2010 altogether 41 TGPBB students received their doctoral degrees.

http://www.uta.fi/ibt/tgpbb/

Aspatwar A, Tolvanen ME, Parkkila S Phylogeny and expression of carbonic anhydrase-related proteins. BMC Mol Biol 2010 ;1125 Järvelä S, Rantala I, Rodriguez A, Kallio H, Parkkila S, Kinnula VL, Soini Y, Haapasalo H Specific expression profile and prognostic significance of peroxiredoxins in grade II-IV astrocytic brain tumors.

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INSTITUTE OF BIOMEDICAL TECHNOLOGY

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Multidisciplinary expertise in Multidisciplinary expertise in

life science science life Tampere University of Technology (TUT) and University of

Tampere (UTA) have a long tradition of high-level research and education related to life sciences and medical technology. Over 250 scientists in various departments have for many years conducted research and education in the fields of cell and molecular biology, genetics, biomaterials, biosensors, computational systems, biotechnology, biomedical engineering, and regenerative medicine. At the beginning of 2011 the two Universities agreed to start the integration of these activities and establish a combined organization, BioMediTech. BioMediTech, a joint institute of TUT and UTA, brings together a powerful mix of multidisciplinary expertise in life sciences and medical technology. The institute aims not only to integrate and strengthen the local tradition of excellence in basic

Excellence in

research

BioMediTech conducts world-class basic and translational research in biomedicine and medical technology. Its research activities cover diverse fields, including biomaterials, stem cells, cancer, immunology, biosensors, imaging, and computational methods, with a common aim of developing personalized medicine via new diagnostic and treatment methods. The institute also houses FinMIT, the Academy of Finland Centre of Excellence in research on mitochondrial disease and ageing.

and, consequently, to produce stem-cell transplants for clinical use. Our adult stem-cell research group pioneered the generation of cranial bone derived from patients’ own fat tissue in 2007. Since then, more than 20 patients have successfully received cranial and facial bone transplants created in this fashion. During the last ten years the research groups of BioMediTech have produced close to 1500 publications in international peer-reviewed journals, nearly 100 patents and over 10 commercial spin-offs.

BioMediTech provides state-of-the-art laboratory and clean-room facilities, and implements relevant quality systems. These have enabled us, for

The institute is funded by national and international agencies such as the Finnish Funding Agency for Technology and Innovation (TEKES), Academy of

example, to be among the first units in the world to initiate stem cell production in compliance with pharmaceutical manufacturing requirements (GMP)

Finland, the Council of Tampere Region, the European Union and its frontier-sciences arm, the European Research Council.

Promoting

Unique

BioMediTech aims to nurture innovation and commercialization of research results via an active patenting policy, by providing expert advice to its scientists on the innovation potential of their discoveries, and by fostering spin-offs. Research

environment

life-science research and teaching, but also to create new platforms for discovery and innovation.

innovation

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educational BioMediTech is also pioneering a unique educational environment by combining UTA-based biosciences and TUT-based technology into a single degree programme, which is planned to start in the autumn

groups participating in BioMediTech have a long history of exploitation of research findings. For example, the Biomedical Engineering unit and its

of 2012. The main objective of the new degree programme will be to educate top-level experts with multidisciplinary skills in life sciences for the

predecessors at TUT were the first in the world to develop bio-absorbable implants such as screws and plates for bone fixation.

demands of both academia and industry.

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Annual Report 2010 Institute of Medical Technology

To the Reader: At the beginning of 2011, Regea Institute for Regenerative Medicine and the Institute of Medical Technology were merged to form the Institute of Biomedical Technology (IBT).

http://www.uta.fi./ibt/ The new Institute cooperates closely with related departments at Tampere University of Technology (TUT). The aim is to create an interdisciplinary, internationally high standard research and education institute - BioMediTech.

BioMediTech, begun its work on August 31, 2011, as a joint institute of Tampere University of Technology and University of Tampere, bringing together a powerful mix of multidisciplinary expertise in life sciences and medical technology. Over 250 scientists conduct research and education in the fields of cell and molecular biology, genetics, biomaterials, biosensors, computational systems, biotechnology, biomedical engineering, and regenerative medicine. The Institute aims not only to integrate and strengthen the local tradition of excellence in basic life-science research and teaching, but also to create new platforms for discovery and innovation.

http://www.biomeditech.fi/

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