Primary biliary cirrhosis: molecular genetics and microbial pathogenesis

原发性胆汁性肝硬化：分子遗传学和微生物发病机制

• 批准号: 8281690
• 负责人: Jochen Mattner
• 金额: $ 25.73万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281690
• 关键词: Acute; Adverse effects; Affect; Alleles; Alphaproteobacteria; Antibodies; Antigen-Presenting Cells; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial Infections; Base Pairing; Blood; California; Cell physiology; Cells; Cessation of life; Chicago; Chromosomes, Human, Pair 3; Chronic; Chronic Phase; Chronic Phase of Disease; Cities; Clinical; Clinical Research; Confidential Information; Congenic Mice; Congenic Strain; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease; Environmental Risk Factor; Etiology; Exhibits; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Glycosphingolipids; Goals; Health; Human; Human Resources; Immune; Inbred NOD Mice; Individual; Infection; Inflammation; Inflammatory; Instruction; Interferons; Interleukin-17; Intervention; Language; Last Name; Lead; Lesion; Life; Liver; Liver Failure; Liver diseases; Mediating; Medical center; Mission; Mitochondria; Modeling; Molecular Genetics; Mus; Names; Natural Immunity; Organ; PTPN22 gene; Pathogenesis; Patients; Pediatric Hospitals; Phagocytes; Pharmaceutical Preparations; Phase; Play; Predisposition; Primary biliary cirrhosis; Principal Investigator; Production; Protein Tyrosine Phosphatase; Public Health; Pyruvate Dehydrogenase Complex; Receptor Signaling; Regulation; Research; Research Design; Research Methodology; Resistance; Respiratory Burst; Risk; Risk Factors; Role; Signal Transduction; Susceptibility Gene; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Universities; Virus Diseases; antigen binding; autoreactive T cell; base; bile duct; congenic; defined contribution; effective therapy; equilibration disorder; immune activation; improved; insight; liver transplantation; microbial; mouse model; novel; novel therapeutics; progenitor; pyruvate dehydrogenase complex E2; response; single molecule

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

描述：参见说明。说明该应用程序的广泛、长期目标和具体目标，并参考以下方面的健康相关性 项目（即与机构使命的相关性）。简明地描述实现这些目标的研究设计和方法。描述 您将用于实现这些目标的基本原理和技术。 此外，用两到三个句子，用通俗易懂的语言描述这项研究与公共卫生的相关性。如果申请获得资助，这 描述将按原样成为公共信息。因此，请勿包含专有/机密信息。不要超出空间 假如。 原发性胆汁性肝硬化 (PBC) 是一种慢性炎症性肝病，通常会进展为肝功能衰竭 除非进行肝移植，否则就会死亡。尽管 PBC 的病因尚不清楚， 众所周知，遗传和环境因素都有影响。最近的临床研究强烈表明 新鞘氨醇芳香菌 (N. aro) 感染与 PBC 的发生特别相关 在易感人群中。利用小鼠模型，我们最近表明 N. aro 感染小鼠 导致 PBC 样肝脏病变的发展，这取决于 IFN-¿ 的产生和 IL-17 通过激活 NKT 和常规 T 细胞。根据我们的初步数据，NOD 小鼠 表达 B6 CD101 等位基因或 CD101 表达缺陷的小鼠表现出比其更严重的 PBC 同源或野生型同窝小鼠，我们认为 CD101 基因位于 Idd10 糖尿病中 编码负共刺激分子表达的基因座是一种新的 PBC 易感性 基因。因此，该提案的总体目标是确定 CD101 在易感性/耐药性中的作用 严重的原发性胆管炎。尽管 CD101 易感性等位基因调节 T 细胞激活的确切机制 和 PBC 未知，我们的初步研究结果支持以下假设：信号传导减弱/改变 NOD 背景上的 B6 CD101 等位基因通过 Vav3 激活介导增强的 T 细胞信号 和/或缺乏 PTPN22 诱导，损害调节性 T 细胞和效应 T 细胞之间的平衡，并导致 增强炎症和肝脏疾病。为了检验这一假设，我们的目标是：1）进一步探讨 N. aro 诱导的 PBC 急性期和慢性期的 CD101； 2）确定是否存在遗传差异 CD101 增加 DC 介导的 NKT 和/或常规 T 细胞的激活，从而对 疾病的慢性期； 3)确定B6中T细胞功能是否存在差异调节 CD101同源小鼠是由CD101介导的Vav3和/或PTPN22调节的改变引起的。 将 CD101 鉴定为 PBC 易感基因将为了解 PBC 的发展提供有价值的见解 治疗这种危及生命的疾病的新疗法，但也可能允许识别常见的 未来临床干预的自身免疫性疾病目标。 绩效站点（组织、城市、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。根据需要使用延续页面以如下所示的格式提供所需信息。 从首席研究员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称 eRA Commons 用户名 项目中的组织角色 Mattner, Jochen JOMATTNER CCHMC PI Wicker, Linda S. lwicker 剑桥大学顾问 Ridgway, William M. RIDGWAY2 匹兹堡大学顾问 格什温，M.埃里克·梅格什温 加州大学 戴维斯 顾问 Katz, Jonathan JDKATZ CCHMC 顾问 Bezerra, Jorge BEZERRA CCHMC 顾问 Bendelac, A. BENDELAC ​​芝加哥大学 顾问 Hildeman, David DHILDE CCHMC 顾问 匹兹堡大学