MyD88-dependent B cell dysfunction and autoimmunity during chronic liver disease

慢性肝病期间 MyD88 依赖性 B 细胞功能障碍和自身免疫

• 批准号: 9243006
• 负责人: Manoj Thapa
• 金额: $ 10.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-16 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243006
• 关键词: Adaptor Signaling Protein; Affect; Alcohols; Antigen-Antibody Complex; Antinuclear Antibodies; Area; Autoantibodies; Autoimmune Diseases; Autoimmunity; Award; B cell differentiation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Biology; Biomedical Research; Blood; Carbon Tetrachloride; Cell physiology; Cells; Chronic Hepatitis C; Cirrhosis; Clinical; Complex; Data; Dendritic Cells; Disease; Economic Burden; Economics; Educational workshop; Enrollment; Environment; Equilibrium; Experimental Models; Exploratory/Developmental Grant; Fibrosis; Functional disorder; Funding; Gastroenterology; Goals; Grant; Hepatic Stellate Cell; Hepatitis C; Hepatology; Human; Immune; Immune response; Immune system; Immunologics; Immunologist; Immunology; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammatory; Intention; International; Knock-out; Laboratories; Lead; Liver; Liver Fibrosis; Liver diseases; Manuscripts; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Mentors; Modeling; Multidrug Resistance Gene; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Patients; Phenotype; Preparation; Primates; Principal Investigator; Process; Production; Professional Organizations; Publishing; Receptor Activation; Receptor Signaling; Research; Role; Scientist; Series; Serum; Signal Pathway; Signal Transduction; Specimen; T-Lymphocyte; TLR4 gene; TNF gene; Teacher Professional Development; Therapeutic Intervention; Time; Toll-like receptors; Training; Translational Research; Transplantation; Treatment Efficacy; Tretinoin; United States; United States National Institutes of Health; Universities; Virus; Virus Diseases; Work; Writing; alcohol abstinence; base; career; career development; cell type; certificate program; chronic liver disease; cost; course development; cytokine; design; differentiated B cell; emergency service responder; human tissue; improved; in vivo; insight; intrahepatic; lectures; liver transplantation; meetings; monocyte; mouse model; nonalcoholic steatohepatitis; novel therapeutics; peripheral blood; prevent; programs; response; responsible research conduct; skills; symposium; targeted treatment

PROJECT SUMMARY/ABSTRACT The goal of this NIDDK Mentored Research Scientist Career Development (K01) Award is to provide funding for the principal investigator (PI), Dr. Manoj Thapa, developing into an independent biomedical research scientist in the field of liver disease and liver immunology. After joining the Dr. Arash Grakoui’s laboratory at Yerkes National Primate Research Center of Emory University, the PI initiated a new project with the intention of identifying factors that lead to T and B cell differentiation during liver disease. In this K01 proposal, PI will build upon his previous expertise and study the dynamics of cellular immune responses focusing on the mechanisms of B cell dysregulations during chronic liver diseases associated with chronic hepatitis C virus (HCV) infection, alcohol liver disease (ALD) and nonalcoholic steatohepatitis (NASH). PI will be allocating 75% of his time for the research as proposed in this K01 application and 25% of the time to didactic trainings such as participation in seminars, lab meetings, manuscript preparation, grant writing, and national and international conferences. This project will focus on the contribution of MyD88-specific toll like receptor (TLR) activation and BAFF/BLyS signaling in the B cell-mediated pathogenesis of liver disease and autoimmune disorder. The incidence of end- stage liver disease (ESLD) is increasing in the United States and poses a serious economic and clinical burden as it is expected to afflict more than 300 million individuals worldwide. Chronic HCV infection, ALD, and NASH account for the majority of ESLD cases, with chronic HCV associated with the highest incidence of liver transplantation. The orthotopic liver transplantation is the optimal treatment for ESLD and carries a high cost while benefitting relatively few. Understanding the mechanisms of the cellular immune responses that contributes to fibrosis and the progression of ESLD is critical for effective therapeutic intervention. PI will approach these questions from two different directions. First, by using murine models of experimental liver fibrosis, PI will delineate the role of MyD88-specific TLR signaling and BAFF/BLyS signaling in B cell dysfunction, liver fibrosis and autoimmune disorder associated with liver disease. Then, he will build his career into human translational science to improve an understanding of cellular immune response in human chronic liver diseases including HCV, ALD and NASH patients. These diseases while different have common themes (i.e. fibrosis/cirrhosis) and therefore proposed in this study to compare and contrast the effect of a viral infection (HCV), an inflammation without infection (NASH) and the absence of virus and an on-going inflammatory insult at the time of transplant (ALD) (alcohol abstinence is required for a minimum of 6 months prior to transplant at Emory Transplant Center) on B cell activation and function. The application will provide an immunological basis for the study of targeting therapeutics to reverse the progression and clinical sequelae of liver fibrosis. During the K01 award, PI plans to further master skills and acquire proficiency in the area of human liver biology, chronic liver disease and liver immunology by participating in didactic courses offered by the Emory University and other recognized professional organizations, training in responsible conduct of research, enrolling in Certificate Program in Translational Research, Junior Faculty Development Course and Faculty Development Lecture Series. PI plans to acquire in-depth trainings in human specimens (liver explants and blood) processing and immunological analysis of human tissues in understanding of the complex interaction between the immune system and the liver in multifactorial disease including liver fibrosis, cirrhosis, ESLD, and autoimmune disorders. In addition, PI also plans to actively participate in weekly or monthly seminar series available at Emory University and attend annual national conferences on Fibrosis, Signaling pathways, Immunology, Liver Diseases, and Hepatitis C Virus (HCV). Furthermore, PI will take advantage of multiple grant-writing workshops available at Emory University and plan to apply for NIH grants via the R21 mechanism in the third year, and R01 in the fourth year submitting revisions as needed during the fourth and fifth years. PI will greatly benefit from a team of mentors including Dr. Arash Grakoui, an expert in HCV infection and liver immunology, Dr. Max Cooper, a foremost B cell immunologist, Dr. Frank Anania, an expert clinician in hepatology and gastroenterology, and Dr. Bali Pulendran, an established immunologist. This group of eminent scientists will provide additional expertise and training needed for the PI to achieve his short-term goal of achieving the scientific independence as well as the long-term goal of becoming an established biomedical research scientist and develop a research program to determine the fundamental questions regarding chronic liver disease and associated autoimmune disorders.

项目总结/摘要 这个NIDDK指导研究科学家职业发展（K 01）奖的目标是提供资金 主要研究者（PI）Manoj Thapa博士，发展成为一个独立的生物医学研究 肝脏疾病和肝脏免疫学领域的科学家。在加入Arash Grakoui博士的实验室后， 埃默里大学耶基斯国家灵长类动物研究中心，PI发起了一个新的项目， 识别导致肝病期间T和B细胞分化的因素。在本K 01提案中，PI将 建立在他以前的专业知识和研究细胞免疫反应的动力学，重点是 慢性丙型肝炎病毒相关性肝病患者B细胞失调的机制 (HCV)感染、酒精性肝病（ALD）和非酒精性脂肪性肝炎（NASH）。PI将分配75% 他的时间的研究提出了在这个K 01应用程序和25%的时间教学培训， 作为参与研讨会，实验室会议，手稿准备，赠款写作，以及国家和国际 两会 本项目将重点研究MyD 88特异性Toll样受体（TLR）激活和BAFF/BLyS对MyD 88表达的影响。 在肝脏疾病和自身免疫性疾病的B细胞介导的发病机制中的信号传导。结束的发生率- 在美国，晚期肝病（ESLD）正在增加，并造成严重的经济和临床负担 因为预计全世界将有3亿多人受到影响。慢性HCV感染、ALD和NASH 占ESLD病例的大多数，慢性HCV与肝脏的最高发病率相关， 移植原位肝移植是治疗终末期肝病的最佳方法，但费用较高 而受益相对较少。了解细胞免疫反应的机制， 导致纤维化，ESLD的进展对于有效的治疗干预至关重要。PI将 从两个不同的方向来探讨这些问题。首先，通过使用小鼠实验肝脏模型， PI将描述MyD 88特异性TLR信号传导和BAFF/BLyS信号传导在B细胞中的作用 功能障碍、肝纤维化和与肝病相关的自身免疫性疾病。然后，他将建立他的职业生涯 人类转化科学，以提高对人类慢性疾病细胞免疫反应的理解。 肝病包括HCV、ALD和NASH患者。这些疾病虽然不同，但有共同的主题 (i.e.纤维化/肝硬化），因此在本研究中提出比较和对比病毒性肝炎的作用。 感染（HCV）、无感染的炎症（NASH）和不存在病毒，以及正在进行的 移植时的炎性损伤（ALD）（需要戒酒至少6个月 在埃默里移植中心移植前）对B细胞活化和功能的影响。该应用程序将提供 免疫学基础的研究，靶向治疗，以扭转进展和临床后遗症， 肝纤维化 在K 01奖项期间，PI计划进一步掌握技能并精通人类肝脏领域 生物学，慢性肝病和肝脏免疫学，通过参加埃默里大学提供的教学课程， 大学和其他公认的专业组织，负责任地进行研究的培训， 参加翻译研究证书课程，初级教师发展课程和教师 发展系列讲座。PI计划获得人体标本（肝脏外植体和 血液）处理和人体组织的免疫分析，以了解复杂的相互作用 免疫系统和肝脏之间的多因素疾病，包括肝纤维化，肝硬化，ESLD， 自身免疫性疾病此外，PI还计划积极参加每周或每月的系列研讨会 可在埃默里大学和参加年度全国会议纤维化，信号通路， 免疫学、肝病和丙型肝炎病毒（HCV）。此外，PI将利用多个 埃默里大学提供的赠款写作研讨会，并计划通过R21机制申请NIH赠款 第三年，R 01在第四年，在第四年和第五年根据需要提交修订。Pi 将大大受益于导师团队，包括Arash Grakoui博士，HCV感染和肝脏专家 最重要的B细胞免疫学家Max库珀博士， 肝脏病学和胃肠病学，以及Bali Pulendran博士，一位知名的免疫学家。这群杰出的 科学家将提供PI所需的额外专业知识和培训，以实现其短期目标， 实现科学独立以及成为一个既定的生物医学的长期目标， 研究科学家，并制定一项研究计划，以确定有关慢性 肝病和相关的自身免疫性疾病。