Biophysical Principles of Peristaltic Phenomena

描述（由申请人提供）：食管运动功能障碍和食管下括约肌（LES）功能障碍影响超过十分之一的40岁以上成人和四分之一的60岁以上成人。了解食管收缩和LES张力的机制可能有助于了解正常功能以及与食管疾病相关的一些变化。我们已经表明，食管（ESO）和LES环形肌的收缩取决于不同的信号转导途径。内源性神经递质乙酰胆碱介导的ESO收缩是由蛋白激酶C（PKC）依赖性途径介导的，但PKC激活的导致肌球蛋白磷酸化和ESO收缩的途径尚不清楚。相反，静息LES张力与低分子量分泌型磷脂酶A2（sPLA 2）的活性和花生四烯酸（AA）的产生相关，花生四烯酸（AA）被代谢为胰高血糖素和血栓烷。这些AA代谢物作用于与G蛋白连接的受体，以诱导磷脂酰肌醇特异性和磷脂酰胆碱特异性磷脂酶的活化、第二信使的产生、PKC的活化和持续收缩的维持。我们已经证明，胰腺样（I组）sPLA 2有助于LES张力，但其他PLA 2（II，V和X组）也可能存在。我们现建议：（A）检查ESO环形肌中PKC激活的收缩机制，并鉴定所涉及的蛋白质和由PKC激活引发并导致肌球蛋白磷酸化和收缩的事件序列;（B）在LES环形肌中，我们将检查1）组I和其它sPLA 2和花生四烯酸代谢物在维持LES张力中的作用，2）PKC激活的收缩机制。与ESO类似，由PKC激活启动并导致肌球蛋白磷酸化和LES收缩的事件顺序尚不清楚。3）我们将检查在初始收缩期间和在持续收缩期间响应于AA代谢物（如PGF 2 α和血栓烷）激活的PKC依赖性收缩途径，AA代谢物参与张力的维持。初步数据表明，一个独特的PKC依赖性途径可能会被激活，在维持紧张，这是不同的途径激活在初始收缩反应。这些数据将有助于了解在正常食管和LES的收缩途径，并可能提供一个基础，更好地了解与一些食管运动障碍的变化。

DESCRIPTION (provided by applicant): 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. We have shown that contraction of esophageal (ESO) and LES circular muscle depends on distinct signal transduction pathways. ESO contraction in response to its endogenous neurotransmitter acetylcholine is mediated by protein kinase C (PKC)-dependent pathways, but the pathways activated by PKC to cause myosin phosphorylation and contraction in ESO are unknown. In contrast resting LES tone is associated with activity of a low molecular weight 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-specific and phosphatidylcholine-specific phospholipases, production of second messengers, activation of PKC and maintenance of sustained contraction. We have demonstrated that a pancreatic like (group I) sPLA2 contributes to LES tone, but other PLA2 (group II, V and X) may also be present. We now propose to: (A) examine PKC-activated contractile mechanism in ESO circular muscle and identify the proteins involved and the sequence of events initiated by PKC activation and resulting in myosin phosphorylation and contraction; (B) in LES circular muscle we will examine, 1) the role of group I and other sPLA2's and of arachidonic acid metabolilites in maintenance of LES tone, 2) PKC-activated contractile mechanisms. Similarly to ESO, the sequence of events initiated by PKC activation and resulting in myosin phosphorylation and LES contraction is unknown, 3) we will examine the PKC-dependent contractile pathways activated during initial contraction and during sustained contraction in response to AA metabolites, such as PGF2alpha and thromboxanes, which participate in maintenance of tone. Preliminary data indicate that a distinct PKC-dependent pathway may be activated during maintenance of tone, which is different from the pathway activated during the initial contractile response. 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.