MUSCLE CONTRACTION IN GALLBLADDERS

描述：(改编自申请者的摘要)致结石胆汁 饱和胆固醇被认为是导致胆囊症的原因之一 动力不足，但胆固醇损害胆囊的机制 目前尚不清楚平滑肌肉的情况。人和土拨鼠的胆囊暴露于 胆固醇饱和胆汁表现出收缩受损的反应 激动剂。这种异常反应先于胆结石的形成。 因此，研究人员建议对该信号进行表征 介导胆囊收缩和松弛的信号转导通路 人和土拨鼠的肌肉，并确定诱发的畸形 通过将胆囊肌暴露在饱和了胆固醇的胆汁中。 首先，研究人员将定义 正常的胆囊肌对激动剂的反应。调查人员将 检查钙和第二信使(1，4，5-肌醇)的来源 利用三磷酸(IP3)-钙调蛋白或二酰甘油-蛋白激酶C 被这些激动剂。 接下来，调查人员将确定肌肉是否暴露在 胆汁中过多的胆固醇导致特异性转导中断 路径(S)。初步数据表明，胆固醇引起的损害可能 最初仅限于细胞膜，因为胆固醇损害了人类 胆囊肌，经皂苷通透后，正常收缩 以响应IP3。调查人员将初步证实这一点 用IP3发现并检测蛋白激酶C依赖的途径 也同样牵涉其中。 然后，调查人员将探索各种可能的机制 胆囊肌的潜在松弛。在这方面， 研究人员将研究去甲肾上腺素、血管活性物质的作用 肠肽，以及组氨酸异亮氨酸多肽 神经递质调节人和草原犬的胆囊松弛。 调查人员将确定cAMP和cAMP增加的相对作用 CGMP，和/或在诱导松弛中IP3的减少，并确定是否 这些第二信使中的任何一个都会受到暴露于 胆固醇饱和的胆汁。 研究人员将在草原犬身上测试胆固醇是否诱导 收缩的损害是渐进的、可预防的或可逆的 要么是能溶解胆固醇的熊去氧胆酸(UDCA)，要么是 阿司匹林，它可能通过抑制胆结石的形成而间接预防胆结石的形成 前列腺素合成。他们认为，这些实验的结果 可能为治疗超重受损的患者提供了理论基础 胆囊壁收缩和胆固醇微晶的UDCA。 他们认为，这些数据可能会阐明胆固醇的致病作用。 在破坏胆囊壁收缩的过程中，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.