Program
Summary
Research in our laboratory focuses on the embryonic development and adult regeneration of the endocrine pancreas, and the relationship of defects in these pathways to the pathophysiology of diabetes mellitus, a disease caused by a deficiency in the production or action of insulin. The beta cells of the endocrine pancreas are the only source of insulin production in the body- therefore the regulation of beta cell mass is pivotal to the development of diabetes and successful therapies aimed at correcting diabetes must impact beta cell growth and/or function. Further support for this focus derives from genetic studies linking monogenic forms of human diabetes to mutations in transcription factors that regulate the development of beta cell mass. A model example is the homeobox transcription factor, IPF-1/PDX-1, that plays critical roles in embryonic pancreas development and in differentiated islet beta cell function in the adult endocrine pancreas. Using cutting edge molecular methods, yeast two hybrid libraries, transgenic and knock-out mice, cDNA microarray, chromatin immunoprecipitation, human genetics, and genomic and proteomic approaches, our current projects include:
1. Characterization of a novel PDX C-terminus Interacting Factor, PCIF1, identified in a yeast two-hybrid screen. PCIF1 is a novel nuclear factor that recruits Pdx1 into a cullin3 based E3 ubiquitin ligase for polyubiquitination and proteasomal degradation. Biochemical, molecular, in vivo and human genetics approaches are being applied to elucidate the role of this novel regulatory molecule.
2. Examining the molecular mechanisms by which the incretin hormone GLP-1 stimulates expansion of beta cell mass, with a particular emphasis on signal transduction and the identification of molecular mechanisms whereby GLP-1 promotes beta cell regeneration and regulates PDX expression.
4. Identifing targets of Pdx1, Pbx and Meis homeodomain factors in the pancreatic ß cell.
Publications Please
visit PubMed for a commplete list of publications.
De Leon DD, Farzad CF, Crutchlow MF, Brestelli J, Tobias J, Kaestner KH, and Stoffers DA : Identification of Transcriptional Targets During Pancreatic Growth after Partial Pancreatectomy and Exendin-4 Treatment Physiological Genomics 24(2): 133-43, Jan 2006.
Lee CS, De Leon DD, Kaestner KH and Stoffers DA: Regeneration of pancreatic islets after partial pancreatectomy does not involve the reactivation of neurogenin3. Diabetes 55(2): 269-72, Feb 2006.
Means AL, Meszoely IM, Suzuki K, Miyamoto Y, Rustgi AK, Coffey RJ Jr, Wright CVE, Stoffers DA, Leach SD: Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132(16): 3767-76, Aug 2005.
Liu AH, Desai BM and Stoffers DA: Structure-function analysis and developmental expression of PCIF1, a novel PDX-1 C terminus interacting factor. Keystone Symposium, "Diabetes Mellitus: Molecular Mechanisms, Genetics and New Therapies", Keystone, CO 2005.
Stoffers DA, Liu AH, Desai BM, Sachdeva M, Oliver-Krasinski J, Claiborn K: Maturity Onset Diabetes of the Young (MODY): Human monogenic diabetes and unraveling genetic transcriptional networks of the beta cell. Proceedings of Keystone Symposium "Diabetes Mellitus: Molecular Mechanisms, Genetics and New Therapies", Keystone, CO 2005 Notes: Symposium presentation.
Desai BM, Farzad C, De Leon DD, Guoping S, Leach SD, Stoffers DA: Mature Pancreatic Acinar Cells Do Not Transdifferentiate into Islet Endocrine Cells after Partial Pancreatectomy In Vivo 65th Annual Scientific Sessions of the American Diabetes Association (228-OR), 2005 Notes: Oral Presentation.
Crutchlow MF, Deng S, Yu M, Bae Y-S, Stoffers DA : Exendin-4 Prolongs Mouse Islet Allograft Function, Promotes Hypoglycemia in the Early Post Transplant Period 65th Annual Scientific Sessions of the American Diabetes Association (100-OR), 2005 Notes: Oral presentation.
Ham JN , Crutchlow MF , Desai BM , Simmons RA, Stoffers DA: Neonatal Exendin-4 administration normalizes islet vascularity in the rat intrauterine growth retardation model: potential role of VEGF. Annual Meeting of the Endocrine Society (PI-9), 2005.
Oliver-Krasinski J, Meinkoth JL, Stoffers DA: Rap1 Is Not Required For Erk Activation By The GLP-1 Receptor Pathway In Ins-1 832/13 Cells. 65th Annual Scientific Sessions of the American Diabetes Association (1759-P ), 2005.
Liu AH, Desai BM, Stoffers DA : Developmental Expression and Structure-Function Regulation of PCIF1, a PDX1 Coregulator. 65th Annual Scientific Sessions of the American Diabetes Association (1674-P), 2005.
