Neural Control of the Gallbladder

胆囊的神经控制

基本信息

批准号：
7649761
负责人：
Gary M Mawe
金额：
$ 37.63万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649761
关键词：
Acute Address Agonist Animals Applications Grants Area Arts Attenuated Bile Acids Bile fluid Calculi Cell membrane Cholecystitis Cholelithiasis Cholestasis Cholesterol Contracts Controlled Environment Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Diet Disease Disease Progression Evaluation Event Experimental Models Foundations Functional disorder Funding GTP-Binding Proteins Gall Bladder Diseases Gallbladder Gallbladder Emptying Goals Grant Hormonal Image Impairment In Vitro Individual Inflammation Inflammatory Response Intestines Knowledge Lead Measurement Mediating Mediator of activation protein Membrane Modeling Motor Mus Muscle Muscle function Nuclear Phase Physiology Preparation Property Prostaglandin-Endoperoxide Synthase Protein Kinase Proteins Receptor Activation Reporting Research Rest Role Salts Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes T-Lymphocyte Techniques Testing Therapeutic Tissues Transgenic Mice Ursodeoxycholic Acid base bile salts cell motility electrical property feeding in vivo Model insight neuroregulation overexpression patch clamp prevent protective effect public health relevance receptor research study response single molecule

项目摘要

DESCRIPTION (provided by applicant): Decreased contractility is a hallmark of gallbladder disorders, and it is associated with inflammation and gallstone formation. Recent reports suggest that decreased gallbladder motility is caused by elevated cholesterol and hydrophobic salts in the bile, and that ensuing inflammation and impairments in gallbladder emptying lead to stone formation. Furthermore, mounting evidence suggests that hydrophilic bile salts may have therapeutic potential by restoring gallbladder smooth muscle (GBSM) contractility and reducing gallstone development and inflammation. Nevertheless, the interrelationships between decreased contractility, inflammation, and gallstone formation are not understood, and this reflects our lack of understanding of the cellular events that lead to decreased resting tone and postprandial contractions in gallbladder disease. This competing renewal will address these fundamental gaps in our knowledge. The overall objectives of this grant application are to: (1) elucidate the cellular and ionic mechanisms by which GBSM contractility is disrupted in gallstone disease, (2) resolve the mechanism by which hydrophobic bile salts interact with GBSM; (3) elucidate the role of inflammation in smooth muscle dysfunction and associated biliary stasis in gallstone disease; and (4) elucidate the role of hydrophilic bile salts in the protection of gallbladder function by preventing or reversing these disruptions. Two experimental models will be used. In one model, we will use wild type and transgenic mice fed a lithogenic (gallstone forming) diet to evaluate the functional changes that occur in GBSM during the progression of gallstone disease in normal mice, mice that do not develop cholecystitis, and mice lacking nuclear or membrane bile acid receptors. We will also evaluate GBSM function in mice fed a lithogenic diet while being treated with the protective hydrophilic bile salt, ursodeoxycholic acid, or a cyclooxygenase inhobitor. The second model involves evaluation of the effects of cholesterol and hydrophobic bile salts applied in vitro to GBSM preparations, with or without prior application of ursodeoxycholic acid. This approach allows us to examine the actions of these compounds individually on GBSM in a controlled environment. This grant proposal involves an integrated approach using state-of-the-art techniques to investigate gallbladder pathophysiology from single molecules to the intact tissue during the progression of disease in the animal. Techniques to be used include Ca2+ imaging of GBSM cells in intact muscle bundles, intracellular and patch clamp recording from intact and isolated GBSM cells, respectively, and muscularis tension measurements. Together with our previous studies on smooth muscle function, we will provide insights on how gallbladder motor function is disrupted leading to biliary stasis, and the relationship between disrupted motor function and inflammation. Furthermore, these studies will elucidate the therapeutic potential of hydrophilic bile salts on GBSM to prevent or reverse cellular changes that underlie decrease gallbladder contractility, and uncover the cellular mechanisms that mediate their actions. PUBLIC HEALTH RELEVANCE: Gallstone disease is an extremely common disorder that involves a decrease in the ability of the gallbladder to contract and empty bile into the intestine, thus leading to gallstone formation. The objectives of this grant application are to understand the cellular mechanisms by gallbladder muscle is disrupted in gallstone disease, and to determine whether and how hydrophilic bile salts can protect the gallbladder from these changes.

描述（由申请人提供）：收缩力下降是胆囊疾病的标志，它与炎症和胆结石形成有关。最近的报告表明，胆囊蠕动减少是由胆汁中胆固醇和疏水性盐升高引起的，随后的炎症和胆囊排空障碍导致结石形成。此外，越来越多的证据表明，亲水性胆汁盐可能具有通过恢复胆囊平滑肌（GBSM）收缩性和减少胆结石形成和炎症的治疗潜力。然而，收缩力下降、炎症和胆结石形成之间的相互关系尚不清楚，这反映出我们对导致胆囊疾病静息张力下降和餐后收缩下降的细胞事件缺乏了解。这种相互竞争的更新将解决我们知识中的这些基本差距。本拨款申请的总体目标是：(1) 阐明胆石病中 GBSM 收缩性被破坏的细胞和离子机制，(2) 解决疏水性胆汁盐与 GBSM 相互作用的机制； (3) 阐明炎症在胆石病中平滑肌功能障碍和相关胆汁淤滞中的作用； (4) 阐明亲水性胆汁盐通过预防或逆转这些破坏来保护胆囊功能的作用。将使用两个实验模型。在一个模型中，我们将使用喂食成石（胆结石形成）饮食的野生型和转基因小鼠来评估正常小鼠、未发生胆囊炎的小鼠和缺乏核的小鼠在胆结石疾病进展过程中 GBSM 发生的功能变化。或膜胆汁酸受体。我们还将评估在用保护性亲水性胆汁盐、熊去氧胆酸或环氧合酶抑制剂治疗的同时喂养生石饮食的小鼠的 GBSM 功能。第二种模型涉及评估体外应用的胆固醇和疏水性胆汁盐对 GBSM 制剂的影响，无论是否预先应用熊去氧胆酸。这种方法使我们能够在受控环境中单独检查这些化合物对 GBSM 的作用。该拨款提案涉及采用最先进技术的综合方法，研究动物疾病进展过程中从单分子到完整组织的胆囊病理生理学。使用的技术包括完整肌束中 GBSM 细胞的 Ca2+ 成像、完整和分离 GBSM 细胞的细胞内和膜片钳记录，以及肌层张力测量。结合我们之前对平滑肌功能的研究，我们将深入了解胆囊运动功能如何被破坏导致胆汁淤滞，以及运动功能破坏与炎症之间的关系。此外，这些研究将阐明亲水性胆汁盐对 GBSM 的治疗潜力，以预防或逆转导致胆囊收缩力下降的细胞变化，并揭示介导其作用的细胞机制。公众健康相关性：胆结石病是一种极其常见的疾病，涉及胆囊收缩和将胆汁排入肠道的能力下降，从而导致胆结石形成。该拨款申请的目的是了解胆囊肌在胆结石疾病中受到破坏的细胞机制，并确定亲水性胆汁盐是否以及如何能够保护胆囊免受这些变化的影响。