The Role of TGF-beta in the pathogenesis of Experimental Biliary Atresia

TGF-β在实验性胆道闭锁发病机制中的作用

• 批准号: 7916847
• 负责人: EVAN P NADLER
• 金额: $ 14.46万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916847
• 关键词: Address; Adult; Animal Model; Biliary Atresia; Binding; Binding Proteins; Child; Complex; Development; Disease; Disease Progression; Family; Fibrosis; Genetic Transcription; Goals; Integrin alpha Chains; Integrin beta Chains; Integrins; Kidney; Ligation; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Lung; Mediating; Mediator of activation protein; Modeling; Mouse Strains; Mus; Pathogenesis; Pathway interactions; Peptides; Phosphotransferases; Plasminogen Inactivators; Play; Protein Family; Proteins; Research Personnel; Role; Time; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; bile duct; connective tissue growth factor; design; effective therapy; liver transplantation; prevent; programs; receptor; research study; treatment strategy

DESCRIPTION (provided by applicant): The goal of this project is to determine the role of transforming growth factor-beta (TGF-beta) in the pathogenesis of biliary atresia. Our initial experiments are designed to establish a durable and reproducible animal model of biliary atresia. We will use these preliminary experiments to determine the time course of TGF-beta activation as well as expression of one of the most important mediators of TGF-beta function, the integrin alpha-v beta-6. This integrin has been shown to mediate TGF-beta function and hepatic fibrosis in an adult mouse bile duct ligation model, and we postulate that it will play a similar role in the fibrosis associated with biliary atresia. Downstream mediators of TGF-beta function will also be evaluated, including the SMAD family of proteins, plasminogen activator inhibitors, and the tissue inhibitors of the metalloproteinases. Subsequent studies will address the role of these mediators. The approach will be to employ different strategies designed to inhibit function of each mediator, and then determine what impact blockade has on the development of the fibrosis associated with biliary atresia. The final set of experiments will investigate whether TGF-beta blockade or blockade of its mediators administered after the onset of biliary atresia has any role in preventing the hepatic cirrhosis associated with the disease. The specific aims are: 1. To determine the extent and time course for expression of activated TGF-beta, integrin alpha-v beta- 6, and other important mediators of TGF-beta function in an animal model of biliary atresia; 2. To determine the role of TGF-beta and its mediators in the pathogenesis of experimental biliary atresia by employing different strategies for inhibiting function; and 3. To determine whether TGF-beta blockade or blockade of its mediators after development of biliary atresia can arrest the progression of the disease. Biliary atresia is a progressive obliteration of the bile ducts and is the most common indication for liver transplantation in children. Current therapy fails to prevent liver failure, and thus fails to prevent the need for liver transplantation, in approximately two-thirds of all children stricken with the disease. This proposal is designed to help determine which mediators are important in the development of the liver failure associated with biliary atresia, and whether blocking these mediators may be useful in preventing liver failure.

描述（由申请人提供）：该项目的目的是确定转化生长因子β（TGF-β）在胆道闭锁发病机理中的作用。我们的最初实验旨在建立胆管闭锁的耐用且可重复的动物模型。我们将使用这些初步实验来确定TGF-β激活的时间过程，以及TGF-β函数最重要的介体之一的表达，即整合素alpha-V beta-6。该整合素已显示可在成年小鼠胆管连接模型中介导TGF-β功能和肝纤维化，我们假设它将在与胆道闭锁相关的纤维化中起类似的作用。还将评估TGF-β功能的下游介质，包括蛋白质的SMAD家族，纤溶酶原激活剂抑制剂和金属蛋白酶的组织抑制剂。随后的研究将解决这些介体的作用。该方法将是采用旨在抑制每个调解人功能的不同策略，然后确定封锁对与胆道闭锁相关的纤维化发展的影响。最后一组实验将调查胆道闭锁发作后的TGF-β封锁还是对其介体的阻滞，在防止与疾病相关的肝肝硬化方面有任何作用。具体目的是：1。确定激活的TGF-β，整合蛋白alpha-Vβ-6的表达程度和时间过程，以及在胆道闭锁动物模型中TGF-β功能的其他重要介体； 2。通过采用不同的抑制功能策略来确定TGF-beta及其介体在实验胆道闭锁的发病机理中的作用；和3。确定胆道闭锁发生后的TGF-β封锁还是对介体的阻滞可以阻止该疾病的进展。胆道闭锁是胆管的进行性闭塞性，是儿童肝移植的最常见指示。目前的疗法无法预防肝衰竭，因此在大约三分之二的患有该疾病的儿童中，大约三分之二的儿童都无法防止肝移植的需求。该提案旨在帮助确定哪些介体对于与胆道闭锁相关的肝脏衰竭的发展很重要，以及阻止这些介质是否可能对预防肝衰竭有用。