Primary biliary cirrhosis: molecular genetics and microbial pathogenesis

说明：请参阅说明。说明应用程序的广泛、长期目标和具体目标，并提及与健康相关的 项目(即与该机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句简单明了的话描述这项研究与公共卫生的相关性。如果应用程序得到资助，则此 原样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空格 但前提是。 原发性胆汁性肝病是一种慢性炎症性肝病，通常进展为肝功能衰竭。 除非进行肝移植，否则会死亡。虽然PBC的病因还不是很清楚， 众所周知，遗传和环境因素都起到了作用。最近的临床研究强烈表明 芳香新磷杆菌(N.aro)的感染与PBC的发生有特殊的联系 在易受感染的个体身上。利用小鼠模型，我们最近已经证明了小鼠感染N.aro 结果导致PBC样肝损害的发生，这依赖于干扰素-β和 IL-17通过激活NKT和常规T细胞。根据我们的初步数据，小白鼠 表达B6 CD101等位基因的小鼠或CD101表达缺陷的小鼠表现出比他们的 无论是同基因还是野生型，我们认为位于Idd10糖尿病内的CD101基因 编码负共刺激分子表达的基因座是一种新的PBC易感性 吉恩。因此，这项建议的总体目标是确定CD101在抗药性/易感性中的作用 严重的PBC。尽管CD101易感等位基因调节T细胞活化的确切机制 和PBC是未知的，我们的初步发现支持这样一种假设，即信号通过 结节背景上的B6 CD101等位基因通过激活Vav3介导增强的T细胞信号 和/或缺乏PTPN22诱导，破坏调节性和效应性T细胞之间的平衡，并导致 增强炎症和肝脏疾病。为了检验这一假说，我们的目标是：1)进一步探索 CD101在急性期和慢性期诱导的PBC；2)确定遗传差异是否在 CD101增加DC介导的NKT和/或常规T细胞的激活，从而增加对 疾病的慢性期；以及3)决定B6中T细胞功能的差异调节 CD101同源基因小鼠是由于CD101介导的Vav3和/或PTPN22调节的改变所致。 CD101是PBC的易感基因，对PBC的发生、发展有重要意义 治疗这种危及生命的疾病的新疗法，但也可能允许识别共同的 自身免疫性疾病未来临床干预的靶点。 演出现场(S)(组织、市、州) 俄亥俄州辛辛那提儿童医院医疗中心 关键人员。请参阅说明。根据需要使用续页，以如下所示的格式提供所需信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称时代共享用户名项目上的组织角色 约翰·约马特纳·CCHMC PiMattner Linda S.lwicker剑桥大学顾问 威廉·M·里奇韦，匹兹堡大学顾问 埃里克·梅格什温·格什温 加州大学伯克利分校 戴维斯 顾问 Jonathan JDKATZ CCHMC顾问Katz 豪尔赫·贝泽拉CCHMC顾问贝泽拉 本德拉克，芝加哥大学顾问 匹兹堡大学CCHMC顾问希尔德曼

DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Primary Biliary Cirrhosis (PBC) is a chronic inflammatory liver disease that usually progresses to liver failure and death unless liver transplantation is performed. Although the etiology of PBC is not well understood, both genetic and environmental factors are known to contribute. Recent clinical studies strongly suggest that infection with Novosphingobium aromaticivorans (N. aro) is specifically associated with development of PBC in predisposed individuals. Utilizing a mouse model, we have recently shown that N. aro infection of mice results in the development of PBC-like liver lesions, which are dependent upon the production of IFN-¿ and IL-17 through activation of NKT and conventional T cells. Based on our preliminary data that NOD mice expressing the B6 CD101 allele or mice deficient in CD101 expression exhibit more severe PBC than their congenic or wildtype littermates, we propose that the CD101 gene, which lies within the Idd10 diabetes locus, that encodes the expression of the negative co-stimulatory molecule is a novel PBC susceptibility gene. Thus the overall goal of this proposal is to determine the role of CD101 in susceptibility/resistance to severe PBC. Although the exact mechanisms by which CD101 susceptibility alleles regulate T cell activation and PBC are unknown, our preliminary findings support the hypothesis that diminished/altered signaling by the B6 CD101 allele on the NOD background mediates enhanced T cell signals through Vav3 activation and/or lack of PTPN22 induction that impair the balance between regulatory and effector T cells and leads to enhanced inflammation and liver disease. To test this hypothesis, we aim to: 1) further explore the role of CD101 in the acute and chronic phases of N. aro-induced PBC; 2) determine whether genetic differences in CD101 increase DC-mediated activation of NKT and/or conventional T cells, and, thereby susceptibility to the chronic phase of disease; and 3) determine whether the differential regulation of T cell function in B6 CD101 congenic mice results from alterations in CD101-mediated regulation of Vav3 and/or PTPN22. Identification of CD101 as a susceptibility gene for PBC should provide valuable insight into the development of novel therapeutics to treat this life-threatening disease, but may also allow the identification of common targets in autoimmune disease for clinical intervention in the future. PERFORMANCE SITE(S) (organization, city, state) Children's Hospital Medical Center Cincinnati, OH KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Mattner, Jochen JOMATTNER CCHMC PI Wicker, Linda S. lwicker University of Cambridge Consultant Ridgway, William M. RIDGWAY2 University of Pittsburgh Consultant Gershwin, M. Eric MEGERSHWIN University of California at Davis Consultant Katz, Jonathan JDKATZ CCHMC Consultant Bezerra, Jorge BEZERRA CCHMC Consultant Bendelac, A. BENDELAC University of Chicago Consultant Hildeman, David DHILDE CCHMC Consultant University of Pittsburgh