BIOPHYSICAL PRINCIPLES OF PERISTALTIC PHENOMENA

描述：食道运动功能障碍和下段食道 括约肌(LES)功能影响超过十分之一的40岁以上成年人和 每四个60岁以上的成年人中就有一个。对这些机制的理解 负责食道收缩和LES音调可能对 了解正常功能，以及与 食道疾病。 初步数据显示，食道收缩对 乙酰胆碱(Ach)可能与M受体激活有关 细胞内磷脂酶诱导磷脂酰胆碱代谢， 甘油二酯(DAG)和花生四烯酸(AA)的生产及活化 一条依赖PKC的途径。静息状态的LES音调可能与 一种低分子胰岛样蛋白(1型)分泌的活性 磷脂酶A2(SPLA2)和花生四烯酸(AA)的产生，这是 代谢成前列腺素和血栓烷。这些AA代谢物作用于 与G蛋白相连的受体诱导磷脂酰肌醇激活- 和磷脂酰胆碱特异的磷脂酶，生产第二 LES循环中的信使、激活PKC和维持收缩 肌肉。介导食道收缩和LES静息的PKC同工酶 然而，语气是不同的。食道收缩取决于 钙离子不敏感的PKC-epsilon，LES音调与激活 依赖于钙离子的PKC-β。收缩机制的探讨 与这些PKC相关联并由其激活是必要的，以便 了解正常的食道和LES功能。因为不同的 PKC-β和PKC-epsilon对Ca++敏感性的一些上游机制 在ESO和LES中PKC的激活可能不同，并可能存在某些机制 被PKCs激活可能是同工酶特异性的。 因此，建议在下一个供资期间调查：a) 依赖于激动剂诱导产生的一连串事件 二酰甘油和花生四烯酸，激活PKC-epsilon和 食管肌收缩。B)负责维护的事件 SPLA2诱导的AA和AA代谢物的产生及其机制 负责激活G蛋白，细胞内磷脂酶， 第二信使的产生和LES音调的维护 PKC依赖途径。 这些数据将有助于理解正常情况下的收缩通路 食道和LES，并可能为更好地理解 与某些食道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.