Loss of functional small bowel surface area due to surgical resection, injury or inflammatory bowel disease leads to an adaptive response in the remnant intestine. However, because the capacity for gut self-renewal is limited, many patients who have lost large amounts of bowel depend upon parenteral nutrition for survival. The long-term goal of the proposed research is to elucidate the molecular regulation of the adaptive response as a basis for designing specific clinical approaches to enhance this process, thereby improving the quality of life by eliminating or reducing the need for parenteral nutrition. A cohort of genes that are induced in the early phase of the adaptive response was cloned using a rat intestinal resection model. Candidates for further studies include the immediate early gene, PC4/TIS7, which may be an important regulator of the adaptive response, and a novel intestine specific cDNA, IRR-219, that is down-regulated in adaptation. The major hypotheses of the application are: (1) PC4/TIS7 expression and down-regulation of IRR-219 are functionally important in adaptation, (2) PC4/TIS7 expression is required for the onset of gut epithelial cytodifferentiation, (3) factors regulating gut PC4/TIS7 expression are likely to be proximal mediators of the adaptive response, and (4) there are distinct gene cohorts that are important in different phases of the response.
Five specific aims are proposed: (1) to determine the function of PC4/TIS7 in intestinal cell lines by inhibiting or increasing its expression, (2) to define the role of PC4/TIS7 in adaptation by inhibiting its expression in vivo, (3) to identify proximal regulators of PC4/TIS7 gene expression in the gut epithelium, (4) to determine the significance of IRR-219 down-regulation in the adaptive response, and (5) to clone and characterize additional genes that are differentially regulated during intestinal adaptation.
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