Research Report 2010 - MDC

Matthew PoyStructure of the GroupGroup LeaderDr. Matthew Poy*Graduate StudentsJiaxuan Chen*Maria Dolaptchieva*Dörte Matthäus*Sudhir Gopal Tattikota*microRNAs and Mechanisms ofMetabolic DiseasesType II diabetes has finally become recognized as a major challenge to global health. It isimperative to improve our understanding of the molecular mechanisms behind this disorderand develop new drug therapies. The pathophysiology of diabetes is undoubtedly complex,typically characterized by hyperglycemia resulting from varying states of insulin resistance andimpaired β-cell function. Oftentimes, the failure to regulate circulating blood glucose levels is aconsequence of the inability to produce sufficient amounts of insulin by the pancreatic β-cells.In our group, we focus on fundamental pathways regulating glucose metabolism and howaltered pancreatic islet physiology contributes to metabolic disorders such as type 2 diabetes.The mechanisms governing gene expression patternsintegrate both transcriptional activation, post-transcriptionalgene silencing, and post-translational modifications.In the last decade the complex picture of generegulation has been extended by the discovery ofmicroRNAs. MicroRNAs are short, approximately 22nucleotide long non-coding RNAs which are thought tobe involved in a number of evolutionary conserved regulatorypathways. Many published reports have clearlyillustrated a role for individual microRNA sequences indevelopmental timing, apoptosis, proliferation, differentiation,and organ development. However, in light ofthe many advances in the fields of microRNAs and RNAinterference, many questions remain concerning thefunctional role of microRNAs in tissues like the pancreaticislet. Our work aims to test the hypothesis thatmicroRNAs expressed in the islet play an important rolein the development and function of pancreatic β-cellsthrough their ability to regulate gene expression. Manydirect targets of microRNAs expressed in the pancreaticislet have never been studied with respect to β-cellbiology and it is important to understand how theycontribute to islet function. Using newly developedmouse models, a molecular understanding of the exactnature of microRNAs is necessary to develop therapeuticstrategies for the treatment of metabolic diseaseslike diabetes.Selected PublicationsPoy, MN, Hausser, J, Trajkovski, M, Braun, M, Collins, S, Rorsman, P, Zavolan,M and Stoffel, M. (2009). miR-375 maintains normal pancreatic α- andβ-cell mass. Proc. Natl. Acad. Sci. USA. 106(14):5813-8.Yi, R, Poy, MN, Stoffel, M, and Fuchs, E. (2008) A skin microRNA promotesdifferentiation by repressing ‘stemness’. Nature. 452(7184):225-29.Wolfrum, C, Poy, MN, and Stoffel, M. (2005) Apolipoprotein M is requiredfor pre-HDL formation, cholesterol efflux to HDL and protects againstatherosclerosis. Nature Med. 11, 418-422.Krek, A*, Grun, D*, Poy, MN*, Wolf, R, Rosenberg, L, Epstein, EJ,MacMenamin, P, da Piedade, I, Gunsalus, KC, Stoffel, M, Rajewsky, N. (2005)Combinatorial microRNA target predictions. Nat. Genet. 37(5):495-500.(* equal contribution)Poy, MN, Eliasson, L, Krützfeldt, J, Kuwajima, S, Ma, X, MacDonald, PE,Pfeffer, S, Tuschl, T, Rajewsky, N, Rorsman, P and Stoffel, M. (2004) Apancreatic islet-specific microRNA regulates insulin secretion. Nature.432(7014):226-30.58 Cardiovascular and Metabolic Disease Research