Surgical Studies of Ontogeny, Aging and the Gut

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DESCRIPTION (provided by applicant): Gastrointestinal (GI) hormones regulate a number of important physiologic functions, including intestinal secretion, motility and digestion of nutrients. In addition, certain intestinal hormones have been shown to stimulate gut mucosal proliferation. Neurotensin (NT), an important regulatory hormone localized to specialized enteroendocrine cells (N cells) of the adult small bowel, facilitates fatty acid translocation and affects gut motility, secretion and mucosal growth. Our studies have identified the NT gene (designated NT/N) as an excellent molecular model to help define the complex differentiation pathways leading to gut development and maturation as well as the process of "dedifferentiation" noted in certain colon cancers. Expression of the NT/N gene is regulated in a strict temporal- and spatial-specific pattern in the GI tract. Induction of NT/N gene expression and NT peptide secretion is regulated by signaling pathways which have yet to be completely defined. NT, acting through its cell-surface receptor (NTR), activates a cascade of signaling pathways, which results in the proliferation of normal gut mucosa. The central hypothesis of our proposal continues to be that NT/N gene expression is developmentally regulated in the gut and is dependent upon a combination of signaling pathways, activation of downstream transcription factors, and, in certain instances, gene methylation; NT peptide secretion may be mediated by similar signaling pathways that regulate gene expression. Identifying these regulatory mechanisms are critical to a better understanding of normal intestinal homeostasis and the function of target tissues that are affected by NT. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) to further elucidate the mechanisms contributing to NT/N expression in vivo, 2) to delineate the signaling mechanisms regulating NT/N gene induction, 3) to define the mechanisms contributing to NT peptide secretion, 4) to further assess proliferative effects of NT in the gut. Understanding the factors regulating NT/N expression and NT peptide secretion will provide novel and important information regarding the function of an important intestinal hormone and its effects on target tissues, such as normal gut mucosa. The in-depth analysis of the cellular processes leading to the expression of the "model" intestinal gene NT/N will provide a better understanding of normal gut development and function as well as possibly defining certain cellular events leading to gut neoplasia.