CHOLECYSTOKININ MECHANISMS IN CONTROL OF FOOD INTAKE

描述(改编自摘要)：这是一个新的应用程序寻求 三年的支持，以确定内源性CCK 影响食物的摄入量。胆囊收缩素(CCK)是一种被发现的多肽 在整个大脑以及肠道的神经元和内分泌细胞中。近期 研究表明，CCK-A受体拮抗剂地西吡特 穿透血/脑屏障，刺激各种 物种提供了令人信服的证据，表明CCK是一个重要的饱腹感因素。 然而，无论CCK是在外周、在大脑内还是在 产生饱腹感的多个外围和中心位置仍有待于 下定决心。最近的工作证明了CCK-A受体的存在 迷走神经传入神经元，外源性激活迷走神经传入神经元 CCK，以及外源性CCK和十二指肠营养素的减毒作用 迷走神经损伤对摄食的抑制导致了以下结果 内源性CCK作用假说有待进一步验证 研究：十二指肠上段分泌CCK 营养物质的输送通过旁分泌或神经分泌刺激起作用 肠道迷走感觉神经元产生饱腹感。在建议的 研究首席调查员和他的同事们将使用一种虚假的 喂食大鼠模型(从胃管中摄取食物)来测试这一点 假设。具体目标是：(1)使用受体亚型和部位 特异性CCK拮抗剂(地西平，A70104，CCK单抗， JMV-180)来确定内源性CCK的相对贡献和位置 在调节十二指肠分娩所产生的饱足感中的作用 营养素；(2)利用迷走神经传入神经元的区域特异性损伤 (主干迷走神经Rizoy切开术、迷走神经周围辣椒素切开术、腹腔迷走神经Rizoy切开术)至 评估肠道迷走感觉神经元在调节饱足感中的作用 由十二指肠输送产生的各种营养素；及(3)评估 肠CCK在介导迷走感觉神经元激活中的作用 由十二指肠输送的各种营养物质。在这个项目中，研究人员 将检查外周CCK受体阻断是否使十二指肠萎缩 营养诱导的迷走神经背侧脑干神经元的激活 免疫组织化学检测c-fos的表达。 这些研究将促进我们对CCK机制的理解 摄食量的行为和生理控制。他们还应该 为探索进食的致病机制提供方向 精神障碍及其治疗策略。

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.