PEPTIDE YY--COLONIC GASTRIC AND PANCREATIC INHIBITION

肽YY--结肠胃和胰腺抑制

基本信息

批准号：
3237502
负责人：
IAN L TAYLOR
金额：
$ 10.23万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-06-01 至 1989-05-31
项目状态：
已结题

项目摘要

The goal is to establish the newly discovered ileo-colonic peptide, Peptide YY (PYY), as a true hormone. As PYY has not been approved for use in human subjects, studies will be performed in dogs. The first series of experiments will examine mechanisms of release of PYY. In particular, we will determine whether neural or hormonal messages from the upper intestine determine PYY release or whether direct contact of nutrients with the ileo-colonic mucosa is a necessary prerequisite for release. In the next series of experiments, we will examine the effects of exogeneously infused Peptide YY on th pancreatic secretory response to secretin, cholecystokinin and sham feeding. Other studies will examine the effects of PYY on gastric emptying of liquid and solid meals. In these studies circulating levels of PYY observed during infusion of exogeneous PYY will be compared to those observed after a meal and after the intestinal perfusion of oleic acid to determine if these effects are pharmacological or physiological. We recently demonstrated that PYY specifically inhibits the cephalic phase of acid secretion. To determine if PYY's biological actions are vagal dependent we will examine the effects of vagotomy on PYY's ability to inhibit gastric and pancreatic secretion. In other experiments we will perfuse the ileum and colon with oleic acid and monitor the effects on pancreatic and gastric secretion and on plasma peptide YY concentrations. Additional animals will be prepared with intestinal cannulas so that intestinal contents can be diverted above the ileum to determine the effects of ileo-colonic exclusion on meal stimulated gastric and pancreatic secretion and PYY release. Blood levels of PYY observed under each experimental condition will then be reproduced by infusion of exogenous PYY to determine if PYY explains the altered secretion after ileal perfusion of oleic acid or ileal bypass. Metabolic clearance studies will then be performed to determine if PYY has a metabolic half life comparable to that of established gastrointestinal hormones. Finally, canine PYY will be extracted, purified and the amino acid sequence determined. These studies will determine whether PYY has a physiological or pathophysiological role as a modulator of gastric and pancreatic secretion. They should establish PYY as an enterogastrone with unique characteristics. Finally, they will determine if PYY is the ileo-colonic pancreatic inhibitor, the "pancreatone", or "anti-CCK hormone" described by others.

目标是建立新发现的回结肠肽，Peptide YY（PYY），作为真正的激素。由于 PYY 尚未被批准用于人类受试者，研究将在狗身上进行。第一个系列实验将检查 PYY 的释放机制。特别是，我们将确定来自上肠的神经或激素信息确定 PYY 释放或营养物质是否与回结肠粘膜是释放的必要先决条件。在接下来的通过一系列实验，我们将检查外源性输注的效果肽 YY 对促胰液素、胆囊收缩素的胰腺分泌反应的影响和假喂养。其他研究将检验 PYY 对胃的影响排空液体和固体食物。在这些研究中，循环水平输注外源性 PYY 期间观察到的 PYY 将与输注期间观察到的 PYY 进行比较饭后和肠道灌注油酸后观察确定这些影响是药理学的还是生理学的。我们最近证明 PYY 特异性抑制头期酸分泌。确定 PYY 的生物作用是否是迷走神经作用根据情况，我们将检查迷走神经切断术对 PYY 能力的影响抑制胃和胰腺的分泌。在其他实验中我们将用油酸灌注回肠和结肠并监测对胰腺和胃分泌以及血浆肽 YY 浓度。其他动物将准备好肠插管，以便肠内容物可在回肠上方转移以确定回结肠排斥对膳食刺激胃和胰腺的影响分泌和 PYY 释放。各组下观察到的 PYY 血液水平然后通过输注外源性 PYY 来重现实验条件以确定 PYY 是否可以解释回肠灌注后分泌的改变油酸或回肠旁路。然后将进行代谢清除研究以确定 PYY 的代谢半衰期是否与此相当已确定的胃肠激素。最后，犬PYY将是提取、纯化并测定氨基酸序列。这些研究将确定PYY是否具有生理或病理生理作用作为胃和胰腺分泌的调节剂。他们应该建立 PYY 作为一种具有独特特性的肠胃素。最后，他们将确定 PYY 是否是回结肠胰腺抑制剂其他人描述的“胰酮”或“抗 CCK 激素”。