BIOLOGY
Principal investigator:
Riitta Lahesmaa, M.D., Ph.D., Professor, Turku Centre for Biotechnology, BioCity, Tykistökatu 6A, FI-20521 Turku, Finland. Tel. +358-2-333 8601, Fax. +358-2-333 8000.
Email: [email protected]
Biography:
Riitta Lahesmaa received her M.D. in 1984 and Ph.D. in 1987 from the University of Turku, and was appointed Docent in Immunology in 1990. She was a postdoctoral fellow at Stanford University Medical Center with Professor Lawrence Steinman during the years 1990-1993 (NIH Fogarty Fellowship). In 1994 she moved to Syntex Research Institute (later Roche Bioscience) in Palo Alto, California. As a Principal Scientist she focused on lymphocyte signaling and drug discovery with state-of-the-art functional genomics tools. In 1998 she was appointed Director of Turku Centre for Biotechnology. In 2009 she carried out research in Professor Anjana Rao’s laboratory in Immune Disease Institute, Harvard Medical School, Boston. She also directs BioCity Turku Systems Biology Research Program since 2000.
Personnel:
Senior scientists/ Post-doctoral researchers: Sanna Edelman, Ph.D., Laura Elo-Uhlgren, Ph.D.; Bhawna Gupta, Ph.D.; Riikka Lund, Ph.D.; Robert Moulder, Ph.D.; Juha-Pekka Pursiheimo, Ph.D.; Sunil Raghav, Ph.D.; Omid Rasool, Ph.D.; Emaheswa Reddy, Ph.D.; Johanna Tahvanainen, Ph.D.
Visiting Scientists: David Hawkins, Ph.D. (Ludwig Institute of Cancer Research, San Diego, USA), Kanury Rao, Ph.D., (Director, Immunology Group at ICGEB, New Delhi, India); Brigitta Stockinger, Ph.D. (Principal Investigator, Division of Molecular Immunology, NIMR, London, UK)
Graduate students: Helena Ahlfors, M.Sc.; Sanna Filen, M.Sc. Henna Järvenpää, M.Sc.; Juha Korhonen, M.D.; Minna Kyläniemi, M.Sc. Tapio Lönnberg, M.Sc.; Elisa Närvä, M.Sc.;Mirkka Heinonen, M.Sc. Nelly Rahkonen, M.Sc.; Soile Tuomela, M.Sc. Subhash Tripathi, M.Tech, M.Sc.
Technicians: Marjo Hakkarainen, Sarita Heinonen, Päivi Junni Undergraduate students: Suvi Kantola, Kaarina Ranta, Marjo Linja, Joel Nyström, Juuso Nästi, Verna Salonen
Description of the project :
Our research is focused on molecular systems immunology and stem cell biology. We use holistic genome and proteome wide methods and systems biology to reveal molecular mechanisms of cell signaling, transcriptional and epigenetic programs that determine cell differentiation and fate. These approaches are exploited to understand molecular mechanisms of human immune mediated diseases and certain types of cancer to provide novel therapeutic means to modulate harmful cellular and immune responses.
T helper cell activation and differentiation to functionally distinct subsets Selective activation of T helper (Th) cell subsets plays an important role in the pathogenesis of human allergy and inflammatory diseases. Dissecting pathways and regulatory networks leading to the development of Th1, Th2, Th17 or regulatory T cells (Treg) is essential to understand the pathogenesis of allergy and inflammatory diseases. Th2 cytokines lead to a series of inflammatory processes characteristic for asthma and other atopic diseases whereas Th1 and Th17 cells play a role in the pathogenesis of autoimmune diseases (e.g. type I diabetes). Treg cells have an important role in inhibiting all these T effector cell functions. We have applied a holistic approach to identify genes involved in human Th cell differentiation. Detailed analysis of upstream T Cell Receptor (TCR)/key cytokine receptor induced differentiation will increase our understanding of these processes central for human health and disease and provide novel insights into new therapeutic interventions.
STAT6 is known to be an essential upstream mediator of IL-4R signaling and Th2 differentiation. Importantly, we identified for the first time STAT6 target genes on a genome wide scale in human CD4+ T cells - only small fraction of which were previously known to be STAT-6 regulated. This study, published in Immunity, revealed that in human surprisingly high proportion, up to 80% of IL-4 induced response is STAT6 regulated revealing several new candidates for therapeutic intervention (Elo L et al. 2010). Our studies on IL-4 R signaling in lymphocytes also resulted in identification of new IL4R/STAT-6 regulated proteins in human and mice as well as mechanistic studies on their molecular functions (Aflakian N, et al. 2009, Moulder R. et al. 2010, Tuomela S. et al. 2009, Cho CH et al. 2009). Our results have led to novel hypotheses on the key factors involved in human Th cell differentiation (Lund et al., 2007, Rautajoki et al. 2007). Elucidating their functions further we discovered that ATF3 and SATB1 are important regulators of human Th cell differentiation. ATF3 promotes Th1 differentiation (Filen S. El al. 2010) whereas SATB1 regulates multiple genes during early Th cell differentiation (Ahlfors et al. 2010).
Human embryonic stem cells (hESC) have a unique capacity to differentiate to any type of cell or tissue providing an enormous potential for therapeutic applications. Our recent results based on the use of high resolution microarray technology demonstrate that it is essential to monitor stem cell lines carefully to minimize the risk of malignancies in stem cell therapies. Our study published in Nature Biotechnology and highlighted in Nature Methods revealed that in prolonged culture human embryonic stem cells acquire chromosomal abnormalities and changes in gene expression, many of which are linked to cancer. (Närvä et al. 2010).
Our goal is to elucidate the molecular mechanisms regulating self renewal and pluripotency of hESC and induced pluripotent stem cells (iPS). We have identified novel genes and signaling pathways characteristic for the pluripotent hESC and iPS cells based on a genome wide transcriptome analyses of hESC. Current work aims at further characterization and functional analysis of a panel of selected factors in the maintenance of undifferentiated status of hESC.
Type 1 diabetes (T1D) is the most common metabolic-endocrine disorder in children in western countries and the annual incidence of T1D in Finland is record high. In almost all children, progression to clinical T1D is associated with the presence of β cell specific
autoantibodies. Clinical T1D occurs when 80-90% of the β cells have been destroyed. At this point T1D patient is dependent on a daily insulin substitution for the rest of his/her life and there is a high risk of developing acute and long-term complications. Development of early diagnostics would enable early therapy and possibly preventive treatments resulting in a significant reduction in the health care costs.
Our objective is to study molecular mechanisms of T1D and to discover molecular markers that indicate development of autoimmunity and progression towards clinical T1D. Exploiting the unique biobank of the Type 1 Diabetes Prediction and Prevention Project in Finland (DIPP) we investigated transcriptomic profiles of prospective whole-blood samples from children who have developed T1D-associated autoantibodies and eventually clinical T1D. Gene-level investigation of the data showed systematic differential expression of 520 probesets. A network-based analysis revealed then a highly significant down-regulated network of genes involved in antigen presentation as well as T-cell receptor and insulin signaling. (Elo et al. 2010). Further studies include analysis of larger cohort of longitudinal samples using transciptomics, proteomics and integrating the data with our previous metbolomics results (Oresic et al. 2008).
Funding:
The Academy of Finland, The National Technology Agency of Finland (TEKES), EU 6th framework “ESTOOLS”, JDRF, The Sigrid Jusélius Foundation, The Finnish Cancer Organizations, Turku University Hospital Fund, Graduate Schools (TuBS, DDGS, ISB), University of Turku, Åbo Akademi University, European Research Council, EU 7th framework “SYBILLA”, EU 7th framework “DIABIMMUNE” EU 7th framework “NANOMMUNE”, EraSysBioPlus, European Research Council
Collaborators:
Harri Lähdesmäki (Tampere University of Technology and Aalto University, Reija Autio & Olli Yli-Harja (Tampere University of Technology ), Tero Aittokallio & Olli Nevalainen (UTU), Peter Andrews (University of Sheffield, UK) and the rest of EU FP6 ESTOOLS consortium (Altogether 20 partners), Outi Hovatta (Karolinska Institute, Stockholm, Sweden), Matej Oresic (VTT Technical Research Centre of Finland, Turku), Brigitta Stockinger (NIMR, London, UK and visiting professor at CBT), Kanury V.S. Rao (ICGEB, New Delhi, India and visiting professor at CBT), Anjana Rao (Immune Disease Institute, Harvard Medical School, Boston, MA, USA), Thomas Tushl (Rockefeller University, New York, NY, USA), Christopher Burge (MIT, Cambridge, MA, USA), David Goodlett (University of Washington, Seattle, WA, USA) , Matthias Gstaiger & Ruedi Aebersol (ETZ, Zürich, Switzerland) and the rest of EU FP7 SYBILLA partners (Altogether 14), Panu Jaakkola (Turku Centre for Biotechnology), Olli Simell, Jorma Ilonen & Heikki Hyöty, Juha Kere (Karolinska Institute, Stockholm, Sweden), Bing Ren (Ludwig Institute for Cancer Research, University of California, San Diego, USA), Mikael Knip (University of Helsinki) and the rest of EU FP7 DIABIMMUNE partners (Altogether 12), Bengt Fadeel (Karolinska Institute, Stockholm, Sweden ) and the rest of EU FP7 DIABIMMUNE partners (Altogether 14 partners).
Selected Publications:
Aflakian N, Ravichandran S, Sarwar Jamaal Md. S, Jarvenpää H, Lahesmaa, R, Rao KVS. (2009) Integration of signals from the
B-cell antigen receptor and the IL-4 receptor leads to a cooperative shift in the cellular response axis. Mol Biosyst. 5:1661-71.
Ahlfors H, Limaye A, Elo-Uhlgrén L, Notani D, Gottimukkala K, Burute M, Tuomela S, Rasool O, Galande S* & Lahesmaa R*. (2010) SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation. *Equal contribution.
Blood. 116:1443-53.
Chen, Z., Lund, R., Aittokallio, T., Nevalainen, O. and Lahesmaa, R. (2003) Identification of early, positively and negatively regulated targets of STAT6 in IL-4 stimulated CD4+ T lymphocytes induced to polarize to Th2 cells. J Immunol. 171: 3627-3635.
Cho SH, Goenka S, Henttinen T, Gudapati P, Reinikainen A, Lahesmaa R, Boothby M. (2009) PARP-14, a member of the B aggressive lymphoma (BAL) family, transduces survival signals in primary B cells. Blood. 113:2416-25.
(2007) Systematic construction of gene coexpression networks with applications to human T helper cell differentiation process.
Bioinformatics. 23: 2096-2103.
Elo LL#, Järvenpää H#, Tuomela S#, Raghav S#, Ahlfors H, Laurila K, Gupta B, Lund RJ, Tahvanainen J, Hawkins RD, Orešic M, Lähdesmäki H, Rasool O, Rao KVS*, Aittokallio T*, Lahesmaa R. (2010) IL-4- and STAT6-mediated transcriptional regulation to initiate Th2 program in human T cells. Immunity 32:852-62#, * Equal contribution.
Elo LL*, Mykkänen J*, Nikula T, Järvenpää H, Aittokallio T, Hyöty H, Ilonen J, Veijola R, Knip M, Simell O, Lahesmaa R. (2010) Genome- wide gene expression profiling reveals early suppression of immune response pathways in prediabetic children. *Equal contribution. J
Autoimmun. 35:70-6.
Filén JJ, Filén S, Moulder R, Tuomela S, Ahlfors H, West A, Kouvonen P, Kantola S, Björkman M, Katajamaa M, Rasool O, Nyman TA, Lahesmaa R. (2009)
Mol Cell Proteomics. 8:32-44. Filén S, Ylikoski E, Tripathi S, West A, Björkman M, Nyström J, Ahlfors H, Rao KVS, Coffey E, Rasool O, and Lahesmaa R. (2010) ATF3 is a Positive Regulator of Human IFNG Gene Expression. J
Immunol. 184:4990-9.
Hämäläinen, H., Zhou, H., Chou, W., Hashizume, H., Heller, R. and Lahesmaa R. (2001) Profiling Human Th1 and Th2 Differentiation by High-density Oligonucleotide Arrays. Genome Biology 2 (7): research0022.
Kumar D, Srikanth R, Ahlfors H, Lahesmaa R, Rao K, (2007) Capturing cell-fate decisions from the molecular signatures of a receptor-dependent signaling response. Molecular Systems
Biology. 3:150.
Lund, R., Aittokallio, T., Nevalainen, O. and Lahesmaa, R. (2003) Identification of novel genes regulated by IL-12, IL-4 and TGFb during the early polarization of CD4+ lymphocytes. J. Immunol. 171: 5328-5336.
From left to right, first row: Juha-Pekka Pursiheimo, Emaheswa Reddy, Riikka Lund, Sarita Heinonen, Soile Tuomela, Sanna Edelman, second row: Omid Rasool, Emilia Engström, Nelly Rahkonen, Johanna Tahvanainen, Riina Plosila, Marjo Hakkarainen, Tapio Lönnberg, third row: Subhash Tripathi, Verna Salo, Riitta Lahesmaa.