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

描述（由申请人提供）：本申请的目的是确定胃泌素释放肽（GRP）的生理作用，GRP由胃肠道的肠神经元释放，在大鼠的膳食大小调节中。尽管越来越多的证据支持这种作用，但两个基本问题仍未得到解答：(1)GRP是调节膳食量的生理信号吗？(2)如果GRP确实是一种调节食量的生理信号，那么它是如何做到的呢？这个应用程序通过对存在风险的假设提供一个决定性的测试来解决这些问题：胃泌素释放肽，作为对营养物质的反应而释放，通过首先激活肠道的肠神经来调节食物的大小，而肠神经又激活胃肠道的外源性神经，然后激活后脑背迷走神经复合物的进食控制区域。《四个具体目标》将系统地检验这一假设。(1)确定内源性GRP在调节饲料粒度中的生理作用。(2)确定内源性GRP在胃肠道的作用部位。(3)确定肠道神经元GRP在调节饲料粒度中的作用。(4)确定GRP调节摄食量的传入途径。首先，为了确定GRP在调节正常膳食量中的生理作用，我们将使用无干扰的自发喂养大鼠制备，通过使用舔液计和可靠有效的行为观察量表记录每秒钟的液体饮食摄入量来表征单个膳食。接下来，我们将使用强效的、高选择性的受体拮抗剂和抗体来逆转这种效应。其次，为了确定内源性GRP对食糜大小的胃肠道作用部位，我们将通过动脉封闭输注将GRP输送到器官选择性腹部部位，并测量食糜大小。我们的初步结果表明，GRP的一个作用部位位于胃左动脉的血管床。第三，为了确定肠道神经元在grp调节进食量中的作用，我们将对这些神经元进行化学和手术消融，同时检测fos样免疫反应性（Fos-LI，神经元激活的标记物），同时测量对进食量的影响。第四，为了确定GRP调节进食量的传入通路，我们将对外源性腹神经进行选择性消融（迷走神经切断术、交感神经切断术以及两者同时进行），并测量外源性和内源性GRP对进食量和Fos-LI的反应。在这一应用中，我们提出：(1)GRP在调节饲料粒度方面有重要的生理贡献。(2)胃肠道的肌肠神经元是GRP调节摄食量的作用部位。(3)胃肠道肠神经系统参与GRP对饲料大小的调节。(4)迷走神经和/或交感神经参与肠神经元向后脑传递grp -饱足信号。

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.