Neural Control of the Gallbladder

胆囊的神经控制

• 批准号: 7916581
• 负责人: Gary M Mawe
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916581
• 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

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）：收缩性降低是胆囊疾病的标志，与炎症和胆结石形成相关。最近的报告表明，胆囊运动性降低是由胆汁中胆固醇和疏水盐升高引起的，并且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，亲水性胆盐可能具有治疗潜力，通过恢复胆囊平滑肌（GBSM）的收缩性和减少胆结石的发展和炎症。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，这反映了我们缺乏对胆囊疾病中导致静息张力降低和餐后收缩的细胞事件的理解。这种相互竞争的更新将填补我们知识中的这些根本空白。本基金申请的总体目标是：（1）阐明胆囊结石疾病中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）阐明炎症在胆囊结石疾病中平滑肌功能障碍和相关胆汁淤积中的作用;和（4）阐明亲水性胆汁盐通过预防或逆转这些破坏在保护胆囊功能中的作用。将使用两个实验模型。在一个模型中，我们将使用野生型和转基因小鼠喂食致石（胆石形成）饮食，以评估在正常小鼠、未发生胆囊炎的小鼠和缺乏核或膜胆汁酸受体的小鼠的胆石病进展期间GBSM中发生的功能变化。我们还将评估GBSM在喂食致石饮食的小鼠中的功能，同时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。第二个模型涉及评价胆固醇和疏水性胆汁盐在体外应用于GBSM制剂的影响，有或没有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。这项拨款提案涉及一种综合方法，使用最先进的技术来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。所使用的技术包括完整肌束中GBSM细胞的Ca 2+成像，分别从完整和分离的GBSM细胞进行细胞内和膜片钳记录，以及肌层张力测量。结合我们以前对平滑肌功能的研究，我们将提供关于胆囊运动功能如何被破坏导致胆汁淤积以及运动功能破坏与炎症之间关系的见解。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降低的细胞变化，并揭示介导其作用的细胞机制。公共卫生相关性：胆石病是一种非常常见的疾病，涉及胆囊收缩和排空胆汁进入肠道的能力下降，从而导致胆石形成。这项资助申请的目的是了解胆囊结石疾病中胆囊肌肉被破坏的细胞机制，并确定亲水性胆汁盐是否以及如何保护胆囊免受这些变化的影响。