Digestion is regulated, in part, by peptides released from neurones in the wall of the alimentarey tract. Once released from a nerve ending, a peptide will encounter peptidase enzymes associated with the plasma membranes of adjacent cells or soluble in the interstitial fluid. The peptidases degrade and inactivate the neuropeptides and, in consequence, play a major role in the control of digestive function. However, this aspect of regulation has been a neglected area. This proposal seeks to elucidate the physiological role of neuropeptidases in the regulation of gastric digestion. Attention will be directed to 5 peptides speculated to control gastric motility: substance P, gastrin releasing peptide, cholecystokinin, enkephalin, and vasoactive intestinal polypeptide.
The specific aims are: 1) identification of peptidase in the stomach wall and elucidation of their physiological role in the control of gastric motility; 2) isolation and characterization of peptidases; 3) generation of specific antibodies to localize the enzymes and block enzymatic activities; 4) examination o the factors that may control peptidase expression in the stomach; and 5) synthesis of peptide analogues resistant to degradation and with biological activity. Thorough understanding of the contribution of peptidases to regulation of digestion is important for study of neuropeptide release and function in the tissues and blood, and also will be of clinical importance. Abnormalities in the metabolism of peptides may contribute to disease states. Furthermore, long acting peptide analogues and potent inhibitors of peptide degradation will be of experimental and therapeutic value.
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