BIOPHYSICAL PRINCIPLES OF PERISTALTIC PHENOMENA

描述：食管运动功能障碍和下食管 括约肌（LES）能力影响超过十分之一的40岁以上的成年人， 每四个60岁以上的成年人中就有一个。 对机制的理解 负责食管收缩和LES张力可能有助于 了解正常功能，以及与之相关的一些变化 食道疾病 初步数据表明，食管收缩反应， 乙酰胆碱（Ach）可能与毒蕈碱受体激活有关， 细胞内磷脂酶诱导磷脂酰胆碱代谢， 二酰基甘油（DAG）和花生四烯酸（AA）的产生和活化 PKC依赖性通路的一部分。 静息LES音可能与 活性的低分子量胰腺样（1型）分泌 磷脂酶A2（sPLA 2）和花生四烯酸（AA）的产生， 代谢为胰高血糖素和血栓素。 这些AA代谢物作用于 与G蛋白连接的受体，以诱导磷脂酰肌醇的活化， 和磷脂酰胆碱特异性磷脂酶，产生第二 LES环中PKC的激活和收缩的维持 肌肉. PKC同工酶介导食管收缩和LES静息 但语气却不同。 食管收缩取决于 Ca++-不敏感的PKC-κ B，LES张力与激活的 Ca++依赖性PKC-β。 研究收缩机制 与这些PKC相关并由其激活是必要的， 了解正常食管和LES功能。 因为不同的 PKC-β和PKC-κ上游机制的Ca++敏感性 PKC的激活在ESO和LES中可能存在差异， 可能是同工酶特异性的。 因此，在下一个供资期内，建议调查： 依赖于激动剂诱导产生的事件级联 甘油二酯和花生四烯酸，激活PKC-β， 食管肌收缩。 B）负责维护的事件 sPLA 2诱导AA及其代谢产物产生的机制 负责激活G蛋白，细胞内磷脂酶， 第二信使的产生和LES音调的维持， PKC依赖性通路。 这些数据将有助于了解正常人的收缩途径。 食管和LES，并可能为更好地了解 与某些食管运动障碍相关的变化。

DESCRIPTION: Disorders of esophageal motor function and Lower Esophageal Sphincter (LES) competence affect more than one in ten adults over 40 and one in four adults over 60 years of age. Understanding of the mechanisms responsible for esophageal contraction and LES tone may be useful to understand normal function, and some of the changes associated with esophageal disease. Preliminary data suggest that esophageal contraction in response to acetylcholine (Ach) may be linked to muscarinic receptors activating intracellular phospholipases to induce phosphatidylcholine metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA) and activation of a PKC dependent pathway. Resting LES tone may be associated with activity of a low molecular weight pancreatic-like (type 1) secreted phospholipase A2 (sPLA2) and production of arachidonic acid (AA), which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to G-proteins to induce activation of phosphatidylinositol- and phosphatidylcholine-specific phospholipases, production of second messengers, activation of PKC and maintenance of contraction in LES circular muscle. The PKC isozymes mediating esophageal contraction and LES resting tone, however, are different. Esophageal contraction depends on the Ca++-insensitive PKC-epsilon, LES tone is associated with activation of the Ca++-dependent PKC-beta. Investigating the contractile mechanisms associated with and activated by these PKCs is necessary in order to understand normal esophageal and LES function. Because of the different Ca++-sensitivity of PKC-beta and PKC-epsilon some of the mechanisms upstream of PKC activation may be different in ESO and LES and some mechanisms activated by PKCs may be isozyme specific. In the next funding period it is therefore proposed to investigate: a) the cascade of events which depend upon agonist induced production of diacylglycerol and arachidonic acid, activation of PKC-epsilon and contraction of esophageal muscle. B) the events responsible for maintenance of sPLA2-induced production of AA and AA metabolites, and the mechanisms responsible for activation of G proteins, intracellular phospholipases, production of second messengers and maintenance of LES tone through a PKC-dependent pathway. These data will help in understanding contractile pathways in the normal esophagus and LES, and may provide a basis for better understanding of changes associated with some esophageal motor disorders.