Determining the Mechanisms Regulating Functional Regionalization of the Intestine

Medical College Of Wisconsin, Milwaukee WI

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Abstract

DESCRIPTION (provided by applicant): The mechanisms controlling establishment and maintenance of enterocytes with the capacity to accomplish regionally specific functions are unclear. The long-term goal of our laboratory is to define the regulators and pathways required to create this functional specificity in the intestine and ultimately to manipulate these pathways to control function. Our preliminary studies have shown that loss of the zinc finger transcription factor GATA4 in the jejunum compromises jejunal identity and function suggesting that GATA4 plays a dominant role in conferring jejunal identity. Therefore, the central hypothesis driving this proposal is that restriction of GATA4 along the anterior-posterior axis of the small intestine is required to confer regional specificity to the intestinal epithelium. We propose in Aim 1 to identify the timing of GATA4 restriction along the anterior-posterior axis of the small intestinal epithelium and the extent to which such restriction corresponds with the activation of the jejunal-specific gene expression program. Our studies in Aim 2 will define the mechanisms controlling the restriction of GATA4 along the anterior-posterior axis of the small intestinal epithelium. To determine if GATA4 is sufficient to confer jejunal fate in the intestine, we will ectopically express GATA4 in the ileum, a site where GATA4 is normally absent (Aim 3). Completion of the proposed studies is expected to elucidate the mechanism through which an individual transcription factor acts to regulate regional identity in the intestine. This is significant because these studies will provide knowledge into the basic processes governing the determination of the functional fate of the intestinal epithelium, a prerequisite to the development of novel therapies to combat intestinal failure