Regulation of Stomach Ghrelin

描述（由申请人提供）： 我们的长期工作假设是，最近发现的胃激素，ghrelin，是营养状态的关键信号，生长激素（GH）神经内分泌轴，用于整合能量平衡和生长过程。本研究的主要目的是确定胃饥饿素产生、分泌和作用的生理和分子机制。初步研究结果表明，胃ghrelin的表达和分泌调节饮食和胃肠道和胰腺激素的操作，并有一个胃ghrelin垂体GH轴。我们的具体目标是：目标1。验证胃Ghrelin对垂体GH分泌的调节作用;垂体GH和胃Ghrelin分泌之间存在双向反馈回路; Ghrelin对GH分泌的刺激作用受饮食调节;迷走神经辣椒素敏感纤维参与Ghrelin分泌和Ghrelin激活的GH分泌。目标二。验证胃Ghrelin稳态受胆囊收缩素（CCK）、胰高血糖素和胰岛素样生长因子-1（IGF-I）调节的假设。目标3。描述大鼠和人ghrelin基因的调控元件，并检验调控元件对GH、胰高血糖素和营养素反应的假设。根据初步研究结果，我们希望证明内源性胃ghrelin参与GH分泌的调节，GH对胃ghrelin分泌有反馈作用，ghrelin-GH轴受饮食摄入的调节，ghrelin稳态受CCK、胰高血糖素和IGF-I的调节，GH对胃ghrelin分泌的调节受饮食摄入的调节。生长激素释放肽基因的启动子活性（即生长激素释放肽的产生）受生长激素、胰高血糖素和营养素的调节。营养状况在预测各种分解代谢疾病和Lrauma的存活率方面至关重要。这项研究意义重大，因为我们的研究将阐明生长激素释放肽调节GH分泌的生理和分子机制，并将为治疗体重减轻或增加起关键作用的疾病开辟新的治疗策略。这是一个令人信服的理由来定义生长激素释放肽的生产和分泌的营养调节及其在调节生长激素分泌的作用。

DESCRIPTION (provided by applicant): Our long-term working hypothesis is that the recently discovered stomach hormone, ghrelin, is a critical signal of nutritional status to the growth hormone (GH) neuroendocrine axis serving to integrate energy balance and the growth process. The primary goal of this research is to define physiological and molecular mechanisms underlying the regulation of stomach ghrelin production, secretion and action. Preliminary Findings demonstrate that stomach ghrelin expression and secretion are regulated by dietary and gastrointestinal and pancreatic hormonal manipulations, and that there is a stomach ghrelin-pituitary GH axis. Our Specific Aims are: Aim 1. To test the hypotheses that stomach ghrelin plays a role in the regulation of pituitary GH secretion; that a bi-directional feedback loop exists 3etween pituitary GH and stomach ghrelin secretion; that the stimulatory action of ghrelin on GH secretion is modulated by dietary intake; and that vagal capsaicin sensitive fibers participate in ghrelin secretion and ghrelin-activated GH secretion. Aim 2. To test the hypothesis that stomach ghrelin homeostasis is regulated by cholecystokinin (CCK), glucagon and insulin-like growth factor-1 (IGF-I). Aim 3. To characterize the regulatory elements of the rat and human ghrelin genes and to test the hypotheses that regulatory elements are responsive to GH, glucagon and nutrients. Based upon Preliminary Findings we expect to demonstrate that endogenous stomach ghrelin participates in the regulation of GH secretion, that GH exerts a feedback action on stomach ghrelin secretion and that this ghrelin-GH axis is modulated by dietary intake; that ghrelin homeostasis is regulated by CCK, glucagon and IGF-I; and, that the promoter activity (ie, ghrelin production) of the ghrelin gene is regulated by GH, glucagon and nutrients. Nutritional status is critical in predicting survival in a variety of catabolic diseases and Lrauma. This research is significant because our studies will elucidate physiological and molecular mechanisms behind regulation of GH secretion by ghrelin and will open up new therapeutic strategies for treatment of diseases in which weight loss or gain plays a critical role. This is a compelling reason to define nutritional regulation of ghrelin production and secretion and its role in regulation of GH secretion.