Cellular Decisions of Differentiation in the GI Tract

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The Program Project Grant (PPG)," Cellular Decisions of Differentiation in the GI Tract" integrates the efforts of four investigators (two basic science and two clinical) from three Departments of the University of Michigan Medical School. The central goals of the work proposed in the PPG are: (a) To understand how epithelial cells in the upper gastrointestinal tract acquire their identity, both both with respect to tissue identity (gastric vs. small intestine) and lineage identity (enteroendocrine cell vs. enterocyte or goblet cell) during ontogeny; (b) To investigate how the patterns of cellular differentiation in the acid-secreting epithelium of the stomach are normally controlled through specific intracellularpathways and how these pathways are altered by pathological insults (such insults can cause an alteration in identity of the gastric epithelium, such that it acquires a small intestinal phenoytpe). Subproject #1 examines the cis and trans factors that control identity in the intestinal epithelial cell, from a tissue-specific standpoint (stomach vs intestine), a regional standpoint (duodenum vs. distal intestine)and a differentiation standpoint (crypt vs.tip). In addition, in conjunction with Subprojects #2 and #4, the question of how gene regulation changes when stomach cells acquire intestinal identity (intestinal metaplasia) after pathological insultwill be examined. Subproject #2 will trace the development of the enteroendocrine cell lineage within the intestine using cholecystokinin (CCK) as an early marker for this cell compartment. This work will utilize regulatory transgenes generated in Subproject #1. Subproject #3 will focus on how endogenous growth factors present in the stomach control the pattern of differentiation of the parietal cell. Subproject #4 examines the pathways through which the gastric epithelium responds to inflammation and/or bacterial overgrowth in the stomach throughthe generation of intestinal metaplasia, an alteration in gastric cell identity; the role of the pathways identified in Subproject #3 will be examined. Two Cores will assist the PPG investigators in the performance of Cell Biology techniques (Core A) and with Administration of the program (Core B). Both Cores will enhance the already strong interaction between these four investigators across Departmental lines. Overall, this PPG application will further our understanding of how cells make decisions of identity and differentiation in the stomach and intestine of the GI tract and will provide clues as to how this identity may be altered in pathological states.