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肠道肠神经元释放的胃泌素释放肽（GRP）在大鼠膳食量调节中的生理作用。尽管越来越多的证据支持这种作用，两个基本问题仍然没有答案：（1）GRP是一个生理信号，调节膳食的大小？(2)如果GRP确实是一种调节膳食量的生理信号，那么它是如何做到这一点的呢？本申请通过提供对风险假设的决定性检验来解决这些问题：响应于营养物而释放的胃泌素释放肽通过首先激活肠道的肠神经来调节膳食量，肠神经继而激活胃肠道的外源性神经支配，然后激活后脑背侧迷走神经复合体的进食控制区域。四个具体目标将系统地检验这一假设。(1)确定内源性GRP在调节膳食量中的生理作用。(2)确定负责调节膳食量的内源性GRP的胃肠道作用部位。(3)确定肠神经元GRP在调节膳食量中的作用。(4)确定GRP用于调节膳食量的传入途径。首先，为了确定GRP在调节正常膳食量中的生理作用，我们将使用自发喂养的未受干扰的大鼠制备物，通过使用Lickometers和可靠有效的行为观察量表记录每秒的流质饮食摄入量来表征个体膳食。在此之后，我们将采用有效的，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对膳食量的胃肠道作用部位，我们将通过近动脉输注将GRP输送到器官选择性腹部部位并测量膳食量。我们的初步结果表明，一个网站的作用在于胃左动脉的血管床。第三，为了确定肠神经元在GRP调节膳食量中的作用，我们将采用化学和手术消融这些神经元，结合检测Fos样免疫反应性（Fos-LI;神经元活化的标志物），同时测量对膳食量的影响。第四，为了确定GRP用于调节膳食量的传入途径，我们将进行选择性的外部腹部神经消融（迷走神经切断术、交感神经切除术和两者），并测量响应于外源性和内源性GRP的膳食量和Fos-LI。在这个应用中，我们提出：（1）GRP作出了重要的生理贡献的调节膳食的大小。(2)胃肠道的肌间神经元包括GRP调节膳食量的作用部位。(3)胃肠道的肠神经系统在通过GRP调节膳食量中起作用。(4)迷走神经和/或交感神经在将GRP饱和信号从肠神经元传递到后脑中具有作用。

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.