The gastrointestinal (GI) tract operates as an integrated, coordinated physiological unit to effect the digestion and absorption of nutrients. GI peptide hormones play an essential role in the control of this system through the regulation of endocrine and exocrine secretion and motility as well as epithelial cell growth, differentiation and apoptosis. Our long- term goal is to understand the molecular mechanisms by which peptide hormones exert their effects on the GI tract and associated organs during normal and disease states. Our long-term goal is to understand the molecular mechanisms by which peptide hormones exert their effects on the GI tract and associated organs during both normal and disease states. To achieve this, we will continue to focus our investigations on the peptide bombesin (BBS) and its cognate receptors. During the past 5 years, with support from this grant, we have great strides in understand the molecular mechanisms regulating BBS-stimulated peptide secretion, gene expression and cell growth. We found that BBS, through the activation of specific kinase cascades, regulates the expression of various genes including members of the immediate early gene family, the peptide hormones, neurotensin (NT) and gastrin, and the enzyme, cyclooxgenase- 2. We have defined the roles of cytosolic free Ca2+, protein kinase C and mitogen activated protein kinases in BBS-stimulated secretion of NT and chromogranin A using a model human endocrine cell line, developed in our laboratory, called BON/GRP-R. We have shown that BBS can both stimulate and inhibit cell growth depending on the cellular context. We found that BBS can regulate NIT secretion and that NT enhances the trophic effects of glucagon-like peptide on normal intestinal growth in vivo. We also found that BBS acts synergistically with TGF-beta to induce rat intestinal epithelial cell death by induction of apoptosis in vitro. Based on these findings, the central hypothesis of this proposal is that BBS, through the activation of specific cell-surface receptors and intracellular signaling pathways, acts directly, by altering cellular programs of gene expression, and indirectly, by stimulating the release of bioactive agents (i.e., mitogenic peptide hormones and prostaglandins), to modulate the growth of normal and neoplastic cells of GI tract. We will examine this hypothesis with three Specific Aims: 1) To determine the cellular factors and signaling pathways mediating BBS-stimulated gene expression. 2) To define the molecular mechanisms involved in BBS- regulated peptide secretion. 3) To examine the molecular mechanisms by which BBS regulates cell proliferation, differentiation and apoptosis. A comprehensive elucidation of the signal transduction systems and molecular mechanisms responsible for the multiple biological effects of BBS-like peptides is crucial to our overall understanding of the diverse biological effects exerted by GI peptide hormones, in general, and should facilitate the development of innovative therapeutic strategies for the treatment of peptide hormone-sensitive diseases.
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