Surgical Studies of Ontogeny, Aging and the Gut

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Gastrointestinal (GI) hormones regulatea numberofimportantphysiologic functions, includingintestinalsecretion,motility and digestion ofnutrients. In addition,certain intestinal hormones havebeen shown to stimulategutmucosal proliferation. Neurotensin (NT), an importantregulatory hormone localized to specialized enterocndocrine cells (Ncells) of theadult small bowel,facilitatesfatty acid translocationand affects gut motility, secretion and mucosal growth. Our studieshave identified the NT gene (designated NT/N) as an excellent molecular model to help define the complex differentiation pathways leading to gut development and maturationas wellas the process of "dedifferentiation" noted incertaincolon cancers. Expression of the NT/N gene is regulated in a strict temporal- and spatial-specific patern 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 proliferationof normal gut mucosa. The central hypothesis of our proposal continues to bethat NT/N gene expression is developmentallyregulatedin the gut and isdependent upon acombinationof signaling pathways, activation of downstream transcription factors, and, in certaininstances,gene methylation; NT peptide secretion may be mediated by similar signalingpathwaysthat regulate gene expression. Identifying these regulatory mechanismsare critical to a better understanding of normal intestinal homeostasis and the function of target tissues that are affected by NT. To examine thishypothesis,we haveplannedexperiments with the following Specific Aims: 1)to further elucidate the mechanisms contributingto NT/N expression in vivo, 2) to delineate the signaling mechanisms regulating NT/N gene induction,3) to define the mechanisms contributingto NT peptide secretion, 4) to further assess proliferateve effects of NT in the gut. Understanding the factors regulating NT/N expression and NT peptide secretion will provide novel and importantinformation regarding the function of an important intestinal hormone and its effects on target tissues, such as normal gut mucosa. The in-depth analysisof the cellular processes leading to the expression of the "model" intest;nal gene NT/N will provide a better understanding of normal gut development and function as well aspossibly defini ngcertain cellularevents leadingto gut neoplasia.