NEUROENDOCRINE REGULATION OF PANCREATIC HORMONE SECRETION

营养诱导的肠缩胆囊素(CCK)分泌的潜在机制尚未完全描述。几个实验室的研究表明，肠道CCK的分泌受到腔内CCK释放因子的刺激。Apelin是多肽家族中最新的成员，该家族通过肠腔内的一种作用来传递肠道CCK分泌的信号。Apelin的独特之处在于，胃apelin在胃的外分泌和内分泌细胞中产生，这意味着apelin通过内分泌和腔内途径引起CCK的分泌。另一个独特的特征是apelin分泌到胃腔而不是肠腔。这一建议检验了胃APELIN作为肠道CCK分泌的生理调节器的假设。为了验证这一假说，通过手术准备的胃和肠灌流大鼠模型，研究确定腔和全身apelin在CCK分泌的生理调节中的重要性。我们的具体目标是：目的1.检验膳食营养素促进胃载脂蛋白分泌的假说。目的2.验证胃Apelin在肠缩胆囊素(CCK)分泌调节中的作用。初步数据显示，胃上皮内有丰富的apelin阳性细胞，肠腔和体循环中含有apelin，apelin在体外和体内都能刺激CCK的分泌，并且apelin的腔免疫中和作用减少了营养诱导的CCK分泌。在目标1中，我们希望证明胃载脂蛋白至少在 两种不同的胃细胞类型，以确定营养诱导的apelin分泌到血浆和腔室，并表明激活壁细胞分泌的配体同时导致apelin释放到胃腔。在目标2中，我们将通过免疫中和作用来确定胃载脂蛋白在营养诱导的CCK分泌中的重要性。鉴于CCK在各种消化疾病和食欲障碍中可能扮演的角色，了解CCK分泌的信号机制是很重要的。更好地了解CCK分泌的调节将有助于理解这些疾病过程的病理生理学，并为新的临床治疗提供洞察力。

Mechanisms underlying nutrient induced intestinal cholecystokinin (CCK) secretion are not completely described. Research from several laboratories show that intestinal CCK secretion is stimulated by luminal CCK releasing factors. Apelin is the newest member of a family of peptides shown to signal intestinal CCK secretion by an action from within the intestinal lumen. Apelin is unique in that gastric apelin is produced in stomach exocrine and endocrine cells implying that apelin acts by endocrine as well as luminal routes to cause CCK secretion. Another unique feature is that apelin is secreted into the stomach lumen rather than the small intestinal lumen. This proposal examines the hypothesis that gastric apelin plays a role as a physiological regulator of intestinal CCK secretion. To test this hypothesis studies are proposed to define the importance of luminal and systemic apelin in the physiological regulation of CCK secretion using surgically prepared stomach and intestinal perfusion rat models. Our Specific Aims are: Aim 1. To test the hypothesis that dietary nutrients activate secretion of gastric apelin. Aim 2. To test the hypothesis that gastric apelin plays a role in the regulation of intestinal cholecystokinin (CCK) secretion. Preliminary data show abundant apelin-positive cells in the stomach epithelium, that the gut lumen and systemic circulation contain apelin, that apelin stimulates CCK secretion in vitro and in vivo in the rat, and that luminal immunoneutralization of apelin decreases nutrient-induced CCK secretion. In Aim 1 we expect to show that gastric apelin is produced in at least two different gastric cell types, to define nutrient-induced apelin secretion into plasma and luminal compartments, and show that ligands which activate parietal cell secretion simultaneously cause apelin release into the gastric lumen. In Aim 2 we will define the importance of gastric apelin in nutrient-induced CCK secretion using immunoneutralization. It is important to understand mechanisms that signal CCK secretion in view of the roles CCK may play in various digestive diseases and appetite disorders. A better appreciation of regulation of CCK secretion will help in understanding the pathophysiology of these disease processes and give insight into new clinical therapies.