A Physiological Role of Gastrin Releasing Peptide in the Control of Meal Size

描述(申请人提供)：本申请的目的是确定胃泌素释放肽(GRP)在调节大鼠进食量方面的生理作用，该释放肽由胃肠道的肠道神经元释放。尽管越来越多的证据支持这种作用，但有两个基本问题仍然没有答案：(1)GRP是调节膳食大小的生理信号吗？(2)如果GRP确实是调节膳食大小的生理信号，那么它是如何做到的？这个应用程序通过提供对风险假设的决定性测试来攻击这些问题：胃泌素释放肽是对营养物质的响应而释放的，通过首先激活肠道的肠神经来调节食物的大小，进而激活胃肠道的外在神经，然后激活后脑背侧迷走神经复合体的摄食控制区。四个具体目标将系统地检验这一假说。(1)确定内源性GRP在调节膳食大小中的生理作用。(2)确定调节膳食大小的内源性GRP的胃肠作用部位。(3)确定肠神经GRP在调节进食中的作用。(4)确定GRP调节膳食大小的传入通路。首先，为了确定GRP在调节正常膳食大小方面的生理作用，我们将使用自发喂养的未受干扰的大鼠制剂来表征个体膳食，方法是使用利克计和可靠有效的行为观察量表记录每秒的液体饮食摄入量。之后，我们将使用有效的、高选择性的受体拮抗剂和抗体来逆转这一效应。其次，为了确定内源性GRP对膳食大小的作用部位，我们将通过近动脉输注将GRP输送到器官选择性的腹部部位，并测量膳食大小。我们的初步结果表明，GRP的作用部位之一位于胃左动脉的血管床上。第三，为了确定肠道神经元在GRP调节进食大小中的作用，我们将使用化学和手术消融这些神经元，并检测Fos样免疫反应(Fos-LI；神经元激活的标志)，同时测量对进食大小的影响。第四，为了确定GRP调节进食大小的传入通路，我们将选择性地消融腹外神经(迷走神经、交感神经切除以及两者兼而有之)，测量外源性和内源性GRP对进食大小和Fos-LI的反应。在这一应用中，我们提出：(1)GRP在调节膳食大小方面做出了重要的生理贡献。(2)胃肠道肌间神经元是GRP调节进食大小的部位。(3)胃肠道的肠道神经系统在GRP调节进食大小中起作用。(4)迷走神经和/或交感神经在肠神经元向后脑传递GRP饱食信号中起作用。 公共卫生相关性：肥胖是一个常见的临床问题，特别是在非裔美国人社区。这种疾病是由于对食物摄入量的控制不善和对调节食物摄入量的过程缺乏了解造成的。这项拟议的研究将调查激素胃泌素释放肽在调节食物摄入量中的作用。

DESCRIPTION (provided by applicant): The goal of this application is to determine the physiological role of gastrin releasing peptide (GRP), released by the enteric neurons of the gastrointestinal tract, in the regulation of meal size in rats. Despite accumulating evidence that support such role, two fundamental questions remain unanswered: (1) Is GRP a physiological signal that regulates meal size? (2) If indeed GRP is a physiological signal that regulates meal size, then how does it do that? This application attacks these questions by providing a decisive test of the hypothesis at risk: Gastrin releasing peptide, released in response to nutrients, regulates meal size by first activating the enteric nerves of the gut, which in turn activates the extrinsic innervation of the gastrointestinal tract and then the feeding control areas of the dorsal vagal complex of the hindbrain. Four Specific Aims will test this hypothesis systematically. (1) Determine the physiological role of endogenous GRP in regulating meal size. (2) Determine the gastrointestinal site of action of endogenous GRP responsible for regulating meal size. (3) Determine the role of enteric neuronal GRP in regulating meal size. (4) Determine the afferent pathway that GRP utilizes to regulate meal size. First, to determine the physiological role of GRP in regulating a normal meal size, we will use the spontaneously feeding undisturbed rat preparation to characterize individual meals by recording second-by-second intakes of liquid diets using lickometers and a reliable and valid behavioral observation scale. Following that, we will employ potent, and highly selective, receptor antagonists and antibodies to reverse the effect. Second, to determine the gastrointestinal site of action of endogenous GRP on meal size we will deliver GRP to organ-selective abdominal sites by close-arterial infusions and measure meal size. Our preliminary results have shown that one site of action of GRP lies in the vascular bed of the left gastric artery. Third, to determine the role of the enteric neurons in GRP-regulation of meal size we will employ chemical and surgical ablations of these neurons combined with detection of Fos-like immunoreactivity (Fos-LI; a marker for neuronal activation) while measuring the effect on meal size. Forth, to determine the afferent pathway that GRP utilizes to regulate meal size we will perform selective ablations of extrinsic abdominal nerves (vagotomy, sympathectomy and both) and measure meal size and Fos-LI in response to exogenous and endogenous GRP. In this application we propose that: (1) GRP makes an important physiological contribution to the regulation of meal size. (2) The myenteric neurons of the gastrointestinal tract comprise the site of action of GRP to regulate meal size. (3) The enteric nervous system of the gastrointestinal tract has a role in the regulation of meal size by GRP. (4) The vagus and / or the sympathetic nerves have a role in transmitting the GRP-satiation signal from the enteric neurons to the hindbrain. PUBLIC HEALTH RELEVANCE: Obesity is a common clinical problem especially in the African American community. This disease results from poor control of food intake and poor understanding of the processes that regulate it. The proposed research will investigate the role of the hormone gastrin releasing peptide in the regulation of food intake.