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Neural Control of Large Intestinal Mucosa

大肠粘膜的神经控制

基本信息

批准号：
6911593
负责人：
HELEN J COOKE
金额：
$ 29.87万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-08-01 至 2007-06-30
项目状态：
已结题

项目摘要

Neural reflexes within the enteric nervous control secretion and motility patterns necessary for appropriate digestive function. Mechanical stimulation release 5- hydroxytryptamine (5-HT) from enterochromaffin cells and binds to 5-HT1P/4 receptors on submucosal afferent neurons in the reflex to cause epithelial chloride secretion. The overall goal is to understand the mechanisms by which a mechanical stimulus applied to the colon is transduced into chloride secretion. Three mechanical stimuli will be used: mucosal stroking, rotational shaking and cell deformation. The 1st aim uses an integrative approach to examine 5-HT release and chloride secretion in muscle-stripped colon from guinea pig, human or nucleotide- receptor deficient mice n response to mechanical stimulation or in a carcinoid tumor cell line, BON. Nucleotides released will be identified, the purinoreceptor subtype classified by agonist/antagonist potencies and the plasma membrane signaling stations known as caveolae identified by electron microscopy. The 2nd aim is to determine whether the purinoceptor in question is dependent on caveolae structure for appropriate signaling during mechanical stimulation. The 3rd aim is to determine if G proteins of the Gq family co-localize with purinoceptors in caveolae to mediate mechanically-evoked 5-HT release in BON cells. For these and subsequent studies immunoprecipitation and immunoblotting techniques will identify the presence of signaling molecules in fractions enriched in caveolae. The 4th aim examines the mechanism involved in mechanical deformation of single BON cells, and determines the role of phospholipase C and intracellular calcium stores in mechanically-evoked 5-HT release. The 5th aim identifies mechanisms by which protein kinase C in modulates mechanically-evoked 5-HT release by examining calcium stores and phosphorylation of phospholipase C. This study with its mechanistic approach from examining integrated systems to the single cell will provide new insights into the regulation of 5-HT release in normal human and animal tissue. It will provide new information about the basic physiology of carcinoid tumors and 5- HT release that may benefit the management of carcinoid syndrome. Understanding the regulation of 5-HT may be a key to management of functional bowel disease associated with an excess or reduced number of enterochromaffin cells.

肠神经内的神经反射控制适当消化功能所必需的分泌和运动模式。机械刺激从肠嗜铬细胞释放5-羟色胺（5-HT），并在反射中与粘膜下传入神经元上的5-HT 1 P/4受体结合，引起上皮氯分泌。总的目标是了解机械刺激施加到结肠被转换成氯分泌的机制。将使用三种机械刺激：粘膜抚摸、旋转摇动和细胞变形。第一个目的是使用一种综合的方法来检查豚鼠、人或核苷酸受体缺陷小鼠的肌肉剥离结肠对机械刺激的反应或类癌肿瘤细胞系BON中的5-HT释放和氯分泌。将鉴定释放的核苷酸，通过激动剂/拮抗剂效力分类嘌呤受体亚型，并通过电子显微镜鉴定称为小窝的质膜信号传导站。第二个目的是确定所讨论的嘌呤受体是否依赖于机械刺激期间适当信号传导的小窝结构。第三个目的是确定Gq家族的G蛋白是否与嘌呤受体共定位在小窝中以介导BON细胞中机械诱发的5-HT释放。对于这些和随后的研究，免疫沉淀和免疫印迹技术将确定在小窝中富集的组分中信号分子的存在。第四个目标是研究单个骨桥细胞机械变形的机制，并确定磷脂酶C和细胞内钙库在机械诱发的5-HT释放中的作用。第五个目标是通过检测钙储存和磷脂酶C的磷酸化来确定蛋白激酶C调节机械诱发的5-HT释放的机制。本研究从整体系统到单细胞的机制研究，将为人类和动物正常组织中5-HT释放的调控提供新的见解。它将提供有关类癌肿瘤的基本生理学和5- HT释放的新信息，可能有利于类癌综合征的治疗。了解5-HT的调节可能是治疗与肠嗜铬细胞数量过多或减少相关的功能性肠病的关键。