? Understanding changes to the molecular features of intestinal epithelial progenitors (IEPs) and their resident niche that occur in response to a variety of environmental and genetic insults will greatly enhance our knowledge of gut disease pathogenesis. For instance, what mechanisms result in the alteration of the normal controls for IEP proliferation during normal, physiologic wound healing? The goal of this application is to build on a recent description of the molecular features of intestinal epithelial progenitors in normal mice and apply this dataset and the techniques used to acquire it to a disease model of epithelial injury of the mouse colon. In this experimental system, epithelial perturbation in the presence of the normal, gut-resident population of microbes (or the """"""""microbiota"""""""") results in a dramatic hyperproliferation of the colonic crypt epithelial cells, while in the absence of the microbiota (using germ-free mice), the epithelial reaction is just the opposite (hypoproliferation). These diametric responses will be used to create two distinct molecular profiles of injury response within separate regions of the colonic mucosa: 1) the colonic epithelial progenitor-rich crypt epithelium and 2) the mesenchymal cells that surround the expanded crypts. RNAs will be isolated from cells procured by laser capture microdissection (LCM) of these specific cellular compartments and functional genomics studies performed. The resulting datasets will provide a molecular picture of signaling pathways active in colonic epithelial stem cells during wound healing and epithelial-mesenchymal crosstalk that occurs during this physiologic response to injury ? ?
| Doherty, Jason M; Geske, Michael J; Stappenbeck, Thaddeus S et al. (2008) Diverse adult stem cells share specific higher-order patterns of gene expression. Stem Cells 26:2124-30 |
| Brown, Sarah L; Riehl, Terrence E; Walker, Monica R et al. (2007) Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J Clin Invest 117:258-69 |
