CHOLECYSTOKININ MECHANISMS IN CONTROL OF FOOD INTAKE

描述（改编自摘要）：这是一个新的应用寻求 三年的支持，以确定通过内源性CCK 影响食物摄入量。 胆囊收缩素（CCK）是一种肽， 遍布大脑和肠道的神经元和内分泌细胞。 最近 研究表明，地伐他啶，一种CCK-A受体拮抗剂， 穿透血/脑屏障，刺激进食， 物种提供了令人信服的证据，CCK是一个重要的饱足感因素。 然而，无论CCK是作用于外周，在大脑内，或在 产生饱腹感的多个外周和中央部位仍然是 测定 最近的工作表明存在的CCK-A受体上 迷走神经传入神经元，外源性刺激对迷走神经传入神经元的激活 CCK和十二指肠营养素诱导的外源性CCK和十二指肠营养素的衰减 通过迷走神经损伤抑制进食导致以下结果 假设内源性CCK的行动，这是由拟议的测试 研究：CCK从上肠分泌，以响应十二指肠 营养物质的输送通过旁分泌或神经分泌刺激起作用， 肠迷走神经感觉神经元产生饱腹感。 拟议 首席研究员和他的同事们将使用一个假的 喂养大鼠模型（摄入的食物从胃插管排出）来测试这一点 假说. 具体目的是：（1）利用受体亚型和位点 特异性CCK拮抗剂（devazepide，A70104，CCK单克隆抗体， JMV-180），以确定内源性CCK的相对贡献和位点 在调节由十二指肠递送各种 营养素;（2）使用迷走神经传入神经元的区域特异性损伤 （迷走神经干切断术、迷走神经周围辣椒素切断术、腹腔迷走神经切断术） 评估肠迷走神经感觉神经元在介导饱腹感中的作用 通过十二指肠递送各种营养素产生;以及（3）评估 肠壁CCK在介导迷走神经感觉神经元激活中的作用 通过十二指肠输送各种营养物质。 在这个项目中，研究人员 将检查外周CCK受体阻滞剂是否能减弱十二指肠 营养素诱导的迷走神经背侧脑干神经元激活 免疫组化检测c-fos表达。 这些研究有助于我们进一步了解CCK的作用机制 行动和食物摄入的生理控制。 他们也应该 为研究进食的致病机制提供了方向 疾病及其治疗策略。

DESCRIPTION (adapted from the Abstract): This is a new application seeking three years of support to identify the actions through which endogenous CCK affects food intake. Cholecystokinin (CCK) is a peptide that is found throughout the brain and in neurons and endocrine cells of the gut. Recent studies demonstrating that devazepide, a CCK-A receptor antagonist that penetrates the blood/brain barrier, stimulates feeding in a variety of species provide compelling evidence that CCK is an important satiety factor. However, whether CCK is acting peripherally, within the brain, or at multiple peripheral and central sites to produce satiety remains to be determined. Recent work demonstrating the existence of CCK-A receptors on vagal afferent neurons, activation of vagal afferent neurons by exogenous CCK, and attenuation of exogenous CCK and duodenal nutrient induced inhibition of feeding by vagal neural lesions has led to the following hypothesis of endogenous CCK's action which is to be tested by the proposed studies: CCK secreted from the upper intestine in response to duodenal delivery of nutrients acts through paracrine or neurocrine stimulation of intestinal vagal sensory neurons to produce satiety. In the proposed research the Principal Investigator and his colleagues will use a sham feeding rat model (ingested food drains from a gastric cannula) to test this hypothesis. The specific aims are: (1) to use receptor subtype and site specific CCK antagonist (devazepide, A70104, CCK monoclonal antibody, JMV-180) to determine the relative contribution and site of endogenous CCK action in mediating the satiety produced by duodenal delivery of various nutrients; (2) to use region-specific lesions of vagal afferent neurons (truncal vagal rizotomy, perivagal capsaicin, celiac vagal rizotomy) to assess the role of intestinal vagal sensory neurons in mediating the satiety produced by duodenal delivery of various nutrients; and (3) to evaluate the role of intestinal CCK in mediating the activation of vagal sensory neurons by duodenal delivery of various nutrients. In this project, the researchers will examine whether peripheral CCK receptor blockade attenuates duodenal nutrient-induced activation of brain stem neurons in the dorsal vagal complex as evidenced by immunohistochemical detection of c-fos expression. These studies should advance our understanding of the mechanisms of CCK actions and the physiological controls of food intake. They should also provide direction in the search for pathogenic mechanisms of eating disorders and strategies for their treatment.