FEEDING AND GI PEPTIDE EFFECT ON HYPOTHALAMIC/PITUITARY/ADRENAL AXIS

进食和胃肠肽对下丘脑/垂体/肾上腺轴的影响

• 批准号: 6107045
• 负责人: LINDA D SANDER
• 金额: $ 7.35万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107045
• 关键词: adrenocorticotropic hormone; arginine vasopressin; bombesin; cholecystokinin; corticotropin releasing factor; gastric inhibitory peptide; gastrins; gastrointestinal function; glucocorticoids; hormone regulation /control mechanism; human tissue; hypothalamic pituitary adrenal axis; laboratory rat; nutrient intake activity; nutrition related tag; radioimmunoassay; radionuclides; secretin; statistics /biometry; stress; tissue /cell culture

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.

该提案所依据的假设是 1) ACTH 作用于 以旁分泌和内分泌方式调节胃肠道功能； 2） 胃窦 G 细胞旁分泌 ACTH 的释放是 受下丘脑垂体功能变化的影响 肾上腺轴以及 3) 垂体和窦的分泌 ACTH 受脑肠肽的影响，脑肠肽分泌于 对进食的反应。拟议的研究，其中 解决这个假设，是我们之前和 当前的工作旨在建立： 具体目标 1 - 刺激/抑制胃窦 ACTH 传统的垂体 ACTH 兴奋剂/抑制剂的分泌 分泌物包括促肾上腺皮质激素释放因子（CRF）、精氨酸 加压素 (AVP)、α-螺旋 CRF(9-41)、曼宁化合物和 糖皮质激素； 具体目标 2 - 脑调节胃窦 ACTH 分泌 - 肠道多肽，例如胃泌素、CCK、铃蟾肽和 VIP； 具体目标 3 - 一天中特定时间/有限的基础和有限调节 进食诱导内源性脑肠肽分泌 ACTH/CORT （通过使用受体拮抗剂）； 具体目标 4 - 一天中特定时间/有限刺激（或 外源性脑肠给药对 ACTH 和 CORT 的抑制作用 肽。 胃窦碎片制剂和原位胃的体外培养 灌注研究将用于实现具体目标 1 和 2， 而脑肠肽或其特定的体内给药 受体拮抗剂对清醒禁食和积极喂养的大鼠会 用于检查具体目标 3 和 4。 目前，已知胃肠道功能的变化会影响 HPA 分泌;已知 CPA 功能的变化会影响 GI 功能 众所周知，所有这些都会受到一天中时间的影响。不过，可用 信息不允许人们将这些观察结果整合成一个 相互依存的行动的凝聚力系统。的履行 拟议的目标应提供一个框架，使我们能够 确定 1) 胃窦 ACTH 发挥作用的程度 传统 HPA 轴的要素以及 2) 喂养如何调节正常 和压力诱导的 HPA 功能。