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: 8471694
• 负责人: Jochen Mattner
• 金额: $ 24.83万
• 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/8471694
• 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 inflammation; 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。说明申请的广泛、长期目标和具体目标，并提及 该项目（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请得到资助， 这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空间 提供了 原发性胆汁性肝硬化（PBC）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，否则死亡。虽然PBC的病因学还不清楚， 已知遗传和环境因素都有影响。最近的临床研究强烈表明， 感染食芳香新鞘氨醇菌（Novosphingobium aromaticivorans（N. aro）与PBC的发展密切相关 在易感人群中。利用小鼠模型，我们最近表明，N。小鼠aro感染 导致PBC样肝脏病变的发展，这取决于IFN-γ的产生， IL-17通过活化NKT和常规T细胞。根据我们的初步数据，NOD小鼠 表达B6 CD 101等位基因的小鼠或CD 101表达缺陷的小鼠表现出比它们更严重的PBC。 同系或野生型同窝仔，我们提出，CD 101基因，这是在Idd 10糖尿病 基因座，编码负性共刺激分子的表达是一种新的PBC易感性 基因因此，本提案的总体目标是确定CD 101在对以下疾病的易感性/耐药性中的作用： 严重PBC。尽管CD 101易感性等位基因调节T细胞活化的确切机制 和PBC是未知的，我们的初步研究结果支持这一假设，即减少/改变信号， NOD背景上的B6 CD 101等位基因通过Vav 3激活介导增强的T细胞信号 和/或缺乏PTPN 22诱导，其损害调节性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。为了验证这一假设，我们的目标是：1）进一步探讨的作用， CD 101在N. aro诱导的PBC; 2）确定是否存在遗传差异， CD 101增加DC介导的NKT和/或常规T细胞的活化，从而增加对CD 101的易感性。 疾病的慢性期;和3）确定是否在B6中T细胞功能的差异调节 CD 101同源小鼠由CD 101介导的Vav 3和/或PTPN 22调节的改变引起。 CD 101作为PBC易感基因的鉴定将为PBC的发展提供有价值的见解。 新的治疗方法来治疗这种危及生命的疾病，但也可能允许识别常见的 自身免疫性疾病中的靶点，用于未来的临床干预。 履约地点（组织、城市、州） 儿童医院医疗中心，俄亥俄州辛辛那提 关键人员。参见说明。根据需要使用续页，以下列格式提供所需信息。 从首席研究员开始。按字母顺序列出所有其他关键人员，姓在前。 名称eRA Commons用户名组织在项目中的角色 约亨·乔马特纳 Wicker，琳达S. lwicker剑桥大学顾问 作者声明：William M. RIDGWAY 2匹兹堡大学顾问 Gershwin，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 Bendelac，A. BENDELAC芝加哥大学顾问 Hildeman，大卫DHILDE CCHMC顾问匹兹堡大学

项目成果

Mechanisms of innate lymphoid cell and natural killer T cell activation during mucosal inflammation.

• DOI: 10.1155/2014/546596
• 发表时间: 2014
• 期刊: Journal of immunology research
• 影响因子: 4.1
• 作者: Nau D;Altmayer N;Mattner J
• 通讯作者: Mattner J

CD101 inhibits the expansion of colitogenic T cells.

• DOI: 10.1038/mi.2015.139
• 发表时间: 2016-09
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Schey R;Dornhoff H;Baier JL;Purtak M;Opoka R;Koller AK;Atreya R;Rau TT;Daniel C;Amann K;Bogdan C;Mattner J
• 通讯作者: Mattner J

Perturbations of mucosal homeostasis through interactions of intestinal microbes with myeloid cells.

通过肠道微生物与骨髓细胞的相互作用扰乱粘膜稳态。

• DOI: 10.1016/j.imbio.2014.11.014
• 发表时间: 2015
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Schey,Regina;Danzer,Claudia;Mattner,Jochen
• 通讯作者: Mattner,Jochen