Following loss of functional small bowel surface area, the residual intestinal epithelium mounts a robust adaptive response, with increased crypt cell proliferation and epithelial cell migration, enhanced villus heights, crypt depths and nutrient and electrolyte absorption. This precisely balanced process is established and maintained by continuous interactions between the epithelium and the underlying stroma. The focus of this application is to examine the role of epithelial-mesenchymal interactions in the regulation of gut adaptation after resection, with the overall goal of designing novel therapies to enhance the gut adaptive response. We have explored the function of tis7, a transcriptional co-regulator, in the gut adaptive response and have expanded our studies to determine the role of Hh signaling in the regulation of small bowel epithelial cell proliferation and the adaptive response. The major hypotheses of this proposal are: 1. Tis7 mediates the adaptive response to loss of small bowel surface area by initiating a gene expression program that enhances both functional and morphometric adaptation. 2. Loss of tis7 blocks these adaptive responses, by inhibiting the increase in nutrient absorption and blocking the increase in crypt cell proliferation.
The Specific Aims of this revised proposal are to: 1. Elucidate the role of tis7 in modulating the adaptive response to small bowel resection. 2. Determine the role of tis7 in modulating nutrient uptake. . Utilizing our tis7 transgenic and tis7-/- mouse models, we will determine the effect of tis7 on nutrient absorption and morphometric responses following resection. Interactions of tis7 with wnt and Hh signaling pathways will be explored. We will identify the mechanisms underlying the changes in fat absorption and adiposity. These studies may identify novel targets for new therapies to enhance small bowel regeneration and function following surgery, and in diseases such as Crohn's disease, ischemia or radiation injury.
Short bowel syndrome is an important cause of morbidity, mortality and health care costs in the United States. Identification of therapies that enhance residual small bowel function and ultimately encourage growth of new intestine are needed for treatment of short bowel syndrome, regardless of the underlying etiology (e.g. from Crohn's disease following resection, post-trauma, or vascular injury). The significance of our proposed studies to health is that we have identified novel pathways that regulate the ability of the intestine to grow and absorb nutrients. We have found that pathways regulated by tis7, a gene that regulates transcription of other genes, can promote intestinal growth and nutrient absorption and calorie storage. These observations may provide avenues for new therapies to enhance functional and regenerative adaptation following loss of functional small bowel surface area
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