Doris A Stoffers MD PhD
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:
- 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.
- 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.
- Elucidating molecular mechanisms underlying islet compensation for diet-induced insulin resistance.
- Identifying targets of Pdx1, Pbx and Meis homeodomain factors in the pancreatic ß cell.