Current Research and Scholarly Interests
Organ development requires mechanisms to establish an integrated, stereotyped tissue pattern from multiple distinct cellular components. Many vital organs derive from the endodermal and mesodermal germ layers to form the gastrointestinal and respiratory tracts, yet little is known about the genetic programs that coordinate steps culminating in proper organ morphogenesis and axial position, cell differentiation and physiologic function. Our goal is to identify and understand the pathways that govern organogenesis of the pancreas, a vital organ with endocrine and exocrine functions.
We are using Drosophila, chicks and mice, organisms accessible to embryological, genetic and molecular methods, to identify cell interactions and signaling pathways that regulate early steps in pancreatic islet development. Some of the pathways active during ontogeny also regulate pancreatic growth during adulthood, and we are studying the role of these genetic pathways in growth control and function of the mature pancreas in mice. Armed with an understanding of the mechanisms regulating normal development of insulin-producing cells and other islet cells, we have been able to differentiate functional glucose-responsive islets from embryonic stem cells and other cell lines. These are capable of rescuing glucose regulation and survival in experimental animal models of diabetes mellitus. We are now using this in vitro culture system to isolate candidate islet stem/precursor populations from adult human stem cell populations. We are also using Drosophila to study neuroendocrine cells that govern metabolism. We have discovered that two cell types, one which produces insulin, the other which produces a glucagon-like peptide called AKH, are crucial regulators of glucose homeostasis in Drosophila. Genetic, biochemical, and electrophysiologic studies are being used to elucidate the programs that control development and function of these cells, which comprise the Drosophila endocrine 'pancreas'. In turn, we expect that these studies will identify important conserved functions that govern islet cell biology.