MUSCLE CONTRACTION IN HUMAN & PRAIRIE DOG GALLBLADDERS

描述：（改编自申请人摘要）致石胆汁 饱和胆固醇被认为有助于胆囊 但胆固醇损害胆囊的机制 平滑肌是未知。 人类和草原犬的胆囊暴露于 胆固醇饱和的胆汁表现出响应于 激动剂 这种异常反应先于胆结石的形成。 因此，研究人员建议对信号进行表征， 介导胆囊收缩和舒张的转导途径 肌肉从人和草原土拨鼠，并确定异常诱导 通过将胆囊肌肉暴露于胆固醇饱和的胆汁。 首先，研究人员将确定转导途径所利用的 胆囊肌对激动剂的反应正常。 调查人员将 检查钙和第二信使（1，4，5-肌醇）的来源 三磷酸（IP 3）-钙调蛋白或二酰基甘油-蛋白激酶C） 这些激动剂。 接下来，研究人员将确定肌肉是否暴露于 胆汁中过量的胆固醇引起特异性转导的破坏 途径。 初步数据表明，胆固醇引起的损伤可能 最初仅限于膜，因为胆固醇损伤的人 胆囊肌在用皂苷渗透后，正常收缩 为了响应IP 3。 调查人员将证实这一初步 发现与IP 3和检查是否蛋白激酶C依赖途径 也有类似的参与。 研究人员将探索各种可能的机制， 胆囊肌肉的潜在松弛 在这方面 研究人员将检查去甲肾上腺素、血管活性物质 肠肽和组氨酸异亮氨酸肽 调节人类和草原犬鼠胆囊松弛的神经递质。 研究人员将确定cAMP增加的相对作用， cGMP和/或IP 3的减少诱导松弛，并确定是否 这些第二信使中的任何一个都受到暴露于 胆固醇饱和的胆汁 研究人员将在土拨鼠身上测试胆固醇诱导的 收缩受损是进行性的、可预防的或可逆的， 熊去氧胆酸（UDCA），其溶解胆固醇，或与 阿司匹林，它可以通过抑制胆结石的形成来间接预防胆结石的形成。 前列腺素合成 他们相信，这些实验的结果， 可能为治疗超重患者提供了理论基础， 胆囊收缩和胆固醇微晶与UDCA。 他们认为，这些数据可能阐明胆固醇的致病作用 破坏胆囊收缩，并可能最终导致 胆固醇结石患者的长期非手术治疗。

DESCRIPTION: (Adapted from the applicant's abstract) Lithogenic bile saturated with cholesterol is thought to contribute to gallbladder hypomotility, but the mechanism whereby cholesterol damages the gallbladder smooth muscle is not known. Human and prairie-dog gallbladders exposed to cholesterol-saturated bile exhibit impaired contraction in response to agonists. This abnormal response precedes the formation of gallstones. Therefore, the investigators propose to characterize the signal transduction pathways mediating contraction and relaxation in gallbladder muscle from man and prairie dog and to determine the abnormalities induced by exposure of gallbladder muscle to bile saturated with cholesterol. First, the investigators will define transduction pathways utilized by normal gallbladder muscle in response to agonists. The investigators will examine the sources of calcium and the second messengers (1,4,5-inositol triphosphate(IP3)-calmodulin or diacylglycerol-protein kinase C) utilized by these agonists. Next, the investigators will determine whether exposure of the muscle to the excess cholesterol in bile causes disruption of specific transduction pathway(s). Preliminary data suggest that cholesterol-induced damage may be initially limited to the membrane, since cholesterol-damaged human gallbladder muscle, after permeabilization with saponin, contracts normally in response to IP3. The investigators will confirm this preliminary finding with IP3 and examine whether the protein kinase C-dependent pathway is similarly involved. The investigators will then explore the various possible mechanisms underlying relaxation in the gallbladder muscle. In this context the investigators will examine the roles of norepinephrine, vasoactive intestinal peptide, and peptide histidine isoleucine as possible neurotransmitters mediating gallbladder relaxation in man and prairie dog. The investigators will determine the relative role of increases in cAMP and cGMP, and/or decreases in IP3 in inducing relaxation, and determine whether any of these second messengers is affected by exposure to cholesterol-saturated bile. The investigators will test in prairie dogs whether cholesterol-induced impairment of contraction is progressive, preventable, or reversible with either ursodeoxycholic acid (UDCA), which solubilizes cholesterol, or with aspirin, which may indirectly prevent formation of gallstones by inhibiting prostaglandin synthesis. The results of these experiments, they believe, may provide a rationale for treating overweight patients with impaired gallbladder contraction and cholesterol microcrystals with UDCA. These data, they believe, may elucidate the pathogenic role of cholesterol in disrupting gallbladder contraction and may ultimately contribute to long-term, nonsurgical treatment of patients with cholesterol stones.