Coopting epigenetic regulators by Aire to maintain immune tolerance

艾尔利用表观遗传调节因子维持免疫耐受

• 批准号: 9013726
• 负责人: Michael R Waterfield
• 金额: $ 20.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013726
• 关键词: Academic Medical Centers; Affect; Alopecia; Antigens; Area; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Binding Proteins; California; ChIP-seq; Childhood; Cholinergic Receptors; Chromatin; Chromatin Structure; Clinical; Collagen Gene; Collagen-Induced Arthritis; Complement; Complex; Data; Defect; Development; Development Plans; Disease; Distant; Educational workshop; Environment; Environmental Risk Factor; Epigenetic Process; Faculty; Fostering; Funding Opportunities; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Histone H3; Histones; Human; Immune Tolerance; Immunology; In Vitro; Knockout Mice; Knowledge; Laboratories; Link; Lysine; MHC Class II Genes; Mediating; Mentorship; Methylation; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Muscle; Mutation; Myasthenia; Nature; Organ; Paper; Pathogenesis; Patients; Physicians; Polyglandular Autoimmune Syndrome Type I; Population; Positioning Attribute; Post-Translational Protein Processing; Prevention; Process; Proteins; Publications; Publishing; Regulator Genes; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Role; San Francisco; Scientist; Single Nucleotide Polymorphism; Specificity; Structure; Syndrome; T-Lymphocyte; Techniques; Thymic Tissue; Thymic epithelial cell; Thymus Gland; Tissues; Training; Transgenic Mice; Universities; activating transcription factor; activating transcription factor 1; autoreactive T cell; base; career; career development; central tolerance; combat; design; gene repression; in vivo; insight; interstitial retinol-binding protein; meetings; mortality; novel; novel therapeutics; pediatric department; prevent; programs; promoter; protein complex; public health relevance; rheumatologist; skills; thymocyte

 DESCRIPTION (provided by applicant): Autoimmune diseases affect approximately 5% of the population and cause significant morbidity and mortality. The exact cause of most autoimmune diseases is unknown but is thought to be due to a combination of environmental and genetic factors. One critical mechanism humans use to prevent autoimmune disease is the process of central tolerance whereby self-reactive T cells are deleted in the thymus. The importance of central tolerance is highlighted by autoimmune polyglandular syndrome type I (APS1), an autosomal recessive monogenic autoimmune syndrome in which affected patients develop multi-organ autoimmunity. The defective gene in APS1 is the autoimmune regulator (AIRE) gene which is responsible for the expression of thousands of tissue-restricted antigens (TRAs) by medullary thymic epithelial cells (mTECs). mTECs present TRAs to developing T cells in the context of MHC class II, enabling the deletion of autoreactive T cells. While Aire is known to be critical for TRA gene expression, the exact mechanism Aire uses to induce TRA genes is unknown. Further understanding of Aire's mechanism of action will yield insights into the pathogenesis of APS1 as well as other more common autoimmune diseases which have recently been linked to AIRE such as rheumatoid arthritis. This career development proposal has two primary goals. First, the candidate outlines a 5-year career development plan to establish an independent research program. Highlights of this plan include mentorship by Dr. Mark Anderson, a committee structured to provide both scientific and career advice during the candidate's progress, didactic coursework, meetings to supplement local opportunities for scientific enrichment and networking, and finally workshops on laboratory management and professional skills. Second, the candidate outlines a 5-year research strategy to examine fundamental questions related to Aire's mechanism of action. Recent studies have identified two novel Aire-interacting proteins previously known to be involved in the epigenetics of gene repression: activating transcription factor 7 interacting protein (ATF7ip) and methyl CpG binding protein 1 (MBD1). Aire's interaction with the ATF7ip/MBD1 protein complex is critical for TRA gene expression and data published in a recent Nature Immunology paper has shown that Aire binds MBD1 for specificity in inducing TRA gene expression. Furthermore, consistent with MBD1's role in TRA gene expression, Mbd1-/- mice develop autoimmunity. Aim 1 will examine the cellular mechanism of MBD1 in immunotolerance. Aim 2 will interrogate the in vivo role of ATF7ip in TRA gene expression and the prevention of autoimmunity. Aim 3 seeks to further define the molecular mechanisms Aire uses to target TRA genes in vivo. The candidate is an MSTP graduate and pediatric rheumatologist at the University of California, San Francisco (UCSF). Though the candidate has a background in immunology, the areas of prior study and techniques previously employed are distant from his current scientific focus. He would, therefore, benefit from the structured period of mentorship and training outlined in the proposal. After completion of the training period, the candidate will continue to develop an independent research program at an academic medical center with the long-term goal of understanding the underlying mechanisms of autoimmune disease. UCSF provides an ideal environment for the training of pediatric physician-scientists. The UCSF Department of Pediatrics has a long track record of fostering the career development of young faculty. In addition, the UCSF immunology program has a unique breadth of immunological expertise with a number of investigators who are leaders in their respective fields. In summary, this proposal will foster the continued development of the candidate's clinical and scientific portfolio. Upon completion of the proposal, the candidate will likely have made a number of original contributions to our understanding of central tolerance and autoimmune disease. The candidate will also be positioned to compete for further funding opportunities as he develops an independent research program.

 描述（由申请人提供）：自身免疫性疾病影响约5%的人口，并导致显著的发病率和死亡率。大多数自身免疫性疾病的确切原因是未知的，但被认为是由于环境和遗传因素的结合。人类用于预防自身免疫性疾病的一个关键机制是中枢耐受过程，其中胸腺中的自身反应性T细胞被删除。中枢耐受的重要性在I型自身免疫性多腺体综合征（APS 1）中得到了强调，APS 1是一种常染色体隐性单基因自身免疫综合征，其中受影响的患者发生多器官自身免疫。APS 1中的缺陷基因是自身免疫调节因子（AIRE）基因，该基因负责胸腺髓上皮细胞（mTEC）表达数千种组织限制性抗原（TRA）。mTEC在MHC II类的背景下将TRA呈递给发育中的T细胞，使得能够删除自身反应性T细胞。虽然已知Aire对TRA基因表达至关重要，但Aire用于诱导TRA基因的确切机制尚不清楚。进一步了解Aire的作用机制将有助于深入了解APS 1以及其他更常见的自身免疫性疾病的发病机制，这些疾病最近与AIRE有关，如类风湿性关节炎。这个职业发展计划有两个主要目标。首先，候选人概述了一个5年的职业发展计划，以建立一个独立的研究计划。该计划的亮点包括马克安德森博士的指导，一个委员会的结构，以提供科学和职业建议，在候选人的进步，教学课程，会议，以补充当地的机会，科学丰富和网络，最后是实验室管理和专业技能的研讨会。第二，候选人概述了一个5年的研究战略，以研究与艾尔的行动机制有关的基本问题。最近的研究已经确定了两个新的Aire相互作用蛋白，以前已知参与基因阻遏的表观遗传学：激活转录因子7相互作用蛋白（ATF 7ip）和甲基CpG结合蛋白1（MBD 1）。Aire与ATF 7ip/MBD 1蛋白复合物的相互作用对于TRA基因表达至关重要，最近发表在Nature Immunology论文中的数据表明，Aire结合MBD 1特异性诱导TRA基因表达。此外，与MBD 1在TRA基因表达中的作用一致，Mbd 1-/-小鼠产生自身免疫。目的1探讨MBD 1在免疫耐受中的细胞机制。目的2探讨ATF 7ip在TRA基因表达和自身免疫预防中的体内作用。目的3旨在进一步确定Aire用于体内靶向TRA基因的分子机制。候选人是一名MSTP毕业生和加州大学旧金山分校弗朗西斯科（UCSF）的儿科风湿病学家。虽然候选人有免疫学的背景，但以前的研究领域和以前使用的技术与他目前的科学重点相去甚远。因此，他将受益于提案中概述的有条理的指导和培训期。培训期结束后，候选人将继续在学术医疗中心开展独立的研究项目，其长期目标是了解自身免疫性疾病的潜在机制。UCSF为儿科医生科学家的培训提供了理想的环境。UCSF儿科系在培养年轻教师的职业发展方面有着悠久的历史。此外，UCSF免疫学计划拥有独特的免疫学专业知识，拥有许多在各自领域处于领先地位的研究人员。总之，该提案将促进候选人的临床和科学组合的持续发展。完成提案后，候选人可能会对我们理解中枢耐受性和自身免疫性疾病做出一些原创性贡献。候选人还将被定位为竞争进一步的资助机会，因为他开发了一个独立的研究计划。