Growth and function of the mammalian endocrine pancreas are regulated by intercellular signaling pathways. Juvenile and adult pancreatic islet cell growth and function adapt to maintain euglycemia in response to host growth, hyperglycemia, insulin resistance and obesity, and failure by the endocrine pancreas to compensate for these states can lead to diabetes mellitus. While control of endocrine pancreas growth and function are crucial for glucose homeostasis, little is known about the genes that maintain pancreatic endocrine cell growth, differentiation, and function to prevent beta-cell failure. The overall goal of this proposal is to elucidate pancreatic intercellular signaling mechanisms that govern islet cell growth and function. This study will focus on Smad2, a gene encoding an essential component in the transforming growth factor-beta (TGF-beta) signaling pathway, which has been previously shown to regulate embryonic pancreas development and adult pancreas function. In mice with a germline Smad2 null allele, generated by conventional gene disruption strategies, embryonic endocrine pancreas development and adult-stage endocrine pancreas function are impaired. Experiments in this application will test the hypothesis that Smad2-mediated TGF-beta signals regulate pancreatic cell interactions that are crucial for pancreatic beta-cell development and function. This proposal's specific aims are to: (1) Elucidate roles of Smad2 in endocrine pancreas growth and function by using recently-developed in vivo gene targeting methods to inactivate Smad2 in a defined set of pancreatic endocrine cells. (2) Determine if Smad2-mediated TGF-beta signals prevent beta-cell failure, by measuring compensatory beta-cell growth and insulin secretion after Smad2 inactivation in insulin resistant animals. (3) Assess changes in pancreatic development and function following Smad2 over-expression in specific pancreatic endocrine cells. (4) Determine if TGF-beta signaling maintains post-natal bet-cell functions, by inactivating Smad2 specifically in adult stage animals using novel in vivo gene disruption methods. Treatment for inadequate beta-cell function, whether from autoimmunity, or from failure to compensate for increased insulin resistance, might be improved by therapies that stimulate beta-cell growth and regulated insulin secretion. The genetic, molecular and physiologic analyses of Smad2-mediated TGF-beta signaling will add to our understanding of the principles of vertebrate organogenesis, and may lead to new cell-replacement strategies for diabetes mellitus.
| Chen, Hainan; Gu, Xueying; Liu, Yinghua et al. (2011) PDGF signalling controls age-dependent proliferation in pancreatic ?-cells. Nature 478:349-55 |
| Rulifson, Ingrid C; Karnik, Satyajit K; Heiser, Patrick W et al. (2007) Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A 104:6247-52 |
| Heit, Jeremy J; Karnik, Satyajit K; Kim, Seung K (2006) Intrinsic regulators of pancreatic beta-cell proliferation. Annu Rev Cell Dev Biol 22:311-38 |
| Smart, Nora G; Apelqvist, Asa A; Gu, Xueying et al. (2006) Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus. PLoS Biol 4:e39 |
| Harmon, Erin B; Apelqvist, Asa A; Smart, Nora G et al. (2004) GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development 131:6163-74 |
| Kim, Seung K; MacDonald, Raymond J (2002) Signaling and transcriptional control of pancreatic organogenesis. Curr Opin Genet Dev 12:540-7 |
| Harmon, E B; Ko, A H; Kim, S K (2002) Hedgehog signaling in gastrointestinal development and disease. Curr Mol Med 2:67-82 |
