BIOPHYSICAL PRINCIPLES OF PERISTALTIC PHENOMENA

食管反流是一种常见的条件，影响儿童和一个在 十个成年人，如果不治疗可能会导致慢性食管炎，误吸 肺炎、食管狭窄和Barretts食管（癌前病变） 条件虽然食管炎是一种多因素疾病， 依赖于不适当的下食管括约肌（LES）松弛，速度 食管清除率、粘膜阻力等因素的影响， LES压力的增加是慢性阻塞性肺病患者的常见结果。 胃灼热 初步数据表明，食管和LES环形肌利用 不同的Ca++来源、磷脂库和信号转导途径 对乙酰胆碱（ACh）的反应。A）在食管肌肉中 乙酰胆碱诱导的收缩需要细胞外Ca++的内流， 与磷脂酰胆碱代谢、甘油二酯的产生有关 (DAG)和花生四烯酸，以及蛋白激酶C（PKC）的活化 依赖路径B）在LES中，肌肉ACh诱导的收缩利用 磷脂酰肌醇代谢引起细胞内Ca ~（++）释放 (PI)和钙调蛋白-肌球蛋白轻链激酶依赖性途径。 另一方面，静息LES张力可能是由于相对较低的基础PI 水解导致亚最大水平的IP 3诱导的钙释放 与甘油二酯相互作用激活PKC。C.诱导后 PI水解的实验性食管炎基础水平几乎 废除，音调大大降低。的信号转导 途径负责LES收缩响应ACh的变化， 一种依赖于IP 3的产生、钙的释放和钙调蛋白 活化为依赖于细胞外钙流入的活化， PKC的激活。 因此，在下一个拨款期内，我们建议研究： 依赖于磷脂酰胆碱水解的级联事件， 二酰基甘油和花生四烯酸的产生，PKC的活化，和 食管肌收缩。B）导致 LES音调的维护和负责从 负责维持钙调素张力的PKC依赖性途径 依赖性途径用于响应ACh。（一）这些变化 发生在急性实验性食管炎模型中的通路，以及 慢性食管炎模型。 这些数据将有助于理解细胞内的信号转导途径。 正常食管和LES，并定义信号的一些变化 与食管炎相关的传导。这些数据可能会提供一些 深入了解酸引起的损伤与 LES和食管功能的改变，并可能最终提供一个 为制定有效的临床策略提供合理的依据。

Esophageal reflux is a common condition that affects children and one in ten adults, and if untreated may result in chronic esophagitis, aspiration pneumonia, esophageal strictures, and Barretts esophagus, a premalignant condition. Although esophagitis is a multifactorial disease that may depend on inappropriate Lower Esophageal Sphincter (LES) relaxation, speed of esophageal clearance, mucosal resistance and other factors, impairment of LES pressure is a common finding in patients complaining of chronic heartburn. Preliminary data suggest that esophageal and LES circular muscle utilize distinct Ca++ sources, phospholipid pools and signal transduction pathways to contract in response to acetylcholine (ACh). A) In esophageal muscle ACh-induced contraction requires influx of extracellular Ca++ and may be linked to phosphatidylcholine metabolism, production of diacylglycerol (DAG) and arachidonic acid, and activation of a protein kinase C (PKC) dependent pathway. B) In LES muscle ACh-induced contraction utilizes intracellular Ca++ release arising from metabolism of phosphatidilinositol (PI), and a calmodulin-myosin light chain kinase-dependent pathway. Resting LES tone on the other hand may be due to relatively low basal PI hydrolysis resulting in submaximal levels of IP3-induced calcium release and interaction with diacylglycerol to activate PKC. C) After induction of experimental esophagitis basal levels of PI hydrolysis are almost abolished and tone is substantially reduced. The signal transduction pathway responsible for LES contraction in response to ACh changes from one which depends on IP3 production, calcium release and calmodulin activation to one which relies on influx of extracellular calcium and activation of PKC. In the next funding period we therefore propose to investigate: A) The cascade of events which depend upon the hydrolysis of phosphatidylcholine, production of diacylglycerol and arachidonic acid, activation of PKC, and contraction of esophageal muscle. B) The events responsible for maintenance of LES tone and the mechanism responsible for a switch from a PKC dependent pathways responsible for maintenance of tone to a calmodulin dependent pathway utilized in response to ACh. C) The changes in these pathways occurring in a model of acute experimental esophagitis, and in a model of chronic esophagitis. These data will help in understanding the signal transduction pathways in the normal esophagus and LES, and define some of the changes in signal transduction associated with esophagitis. The data may provide some insights into the relationships between acid induced damage and alterations in LES and esophageal function, and may eventually provide a rational basis for devising effective clinical strategies.