The hypothesis on which this proposal is based is that 1) ACTH acts in both a paracrine and an endocrine fashion to modulate GI function; 2) that paracrine release of ACTH from gastric antral G cells is influenced by changes in the functioning of the hypothalamic pituitary adrenal axis and that 3) the secretion of both pituitary and antral ACTH are influenced by the brain-gut peptides which are secreted in response to the ingestion of a meal. The proposed studies, which address this hypothesis, are natural extensions of our previous and current work and are designed to establish:
Specific Aim 1 - stimulation/ inhibition of gastric antral ACTH secretion by traditional stimulants/inhibitors of pituitary ACTH secretion including corticotropin releasing factor (CRF), arginine vasopressin (AVP), alpha-helical CRF(9-41), Manning's Compound, and glucocorticoids;
Specific Aim 2 - regulation of gastric antral ACTH secretion by brain- gut polypeptides such as gastrin, CCK, bombesin, and VIP;
Specific Aim 3 - time-of-day specific/limited mediation of basal and feeding-induced ACTH/CORT secretion by endogenous brain-gut peptides (via the use of receptor antagonists);
Specific Aim 4 - time-of-day specific/limited stimulation (or inhibition) of ACTH and CORT by exogenously administered brain-gut peptides. In vitro incubation of antral fragment preparations and in situ gastric perfusion studies will be used to address specific aims 1 and 2, whereas in vivo administration of brain-gut peptides or their specific receptor antagonists to conscious fasted and actively feeding rats will be used to examine Specific Aims 3 and 4. At present, changes in GI function are known to influence HPA secretion; changes in CPA function are known to influence Gl function and all are known to be influenced by time-of-day. However, available information does not allow one to integrate these observations into a cohesive system of inter-dependent actions. The fulfillment of the proposed objectives should provide a framework which will allow us to determine 1) the extent to which gastric-antral ACTH functions as an element of the traditional HPA axis and 2) how feeding modulates normal and stress-induced HPA function.
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