Doris Stoffers, M.D., Ph.D.
Professor
Perelman School of Medicine at the University of Pennsylvania
Medicine
Smilow Center for Translational Research 12-124
Philadelphia,
PA
19104
USA
p. 215-573-5413
· email
Doris Stoffers, M.D., Ph.D. - Investigator Profile
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 and dysregulation of beta cell mass is pivotal to the development of diabetes. Thus, successful therapies aimed at correcting diabetes will likely 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. The emphasis of this laboratory on the Pancreatic Duodenal homeoboX 1 gene (Pdx-1) is driven by three observations: (1) Pdx1 is critically required for the development of all pancreatic lineages, as evidenced by pancreatic agenesis in mice and humans homozygous for null mutations in the Pdx1 gene, (2) human heterozygous mutations in Pdx1 cause monogenic forms of early and late onset diabetes, and (3) Pdx1 is an essential mediator of islet compensation in genetic mouse models of insulin resistance. We propose that elucidating the molecular mechanisms of Pdx1 action in the developing and adult ß cell will result in identification of novel therapeutic targets and strategies for diabetes, through the genetic or pharmacologic manipulation of these targets in vivo to promote endogenous beta cell regeneration or ex vivo to increase the supply and function of the severely limited number of human islets available for transplantation. Understanding these molecular mechanisms will also inform efforts to develop alternate ß cell replacement sources, such as through the guided differentiation of human stem cells or the transdifferentiation of more plentiful mature cell populations. We also strive to understand the mechanisms whereby incretin hormones like GLP-1 improve ß cell function and survival.
Scientific Interests/Keywords
diabetes, insulin, beta cell, pancreas development, transcriptional regulation, signal transduction
