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

基本信息

批准号：
9212100
负责人：
Michael R Waterfield
金额：
$ 22.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/9212100
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 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 Immunologics 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 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 autoreactive T cell autoreactivity base career career development central tolerance clinical candidate combat design gene repression histone modification 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

项目摘要

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（适用提供）：自身免疫性疾病影响大约5％的人口，并引起大量发病率和死亡率。大多数自身免疫性疾病的确切原因尚不清楚，但被认为是由于环境和遗传因素的结合。人类用来预防自身免疫性疾病的一种关键机制是中央耐受性的过程，从而在胸腺中删除了自反应性T细胞。自身免疫性多边形综合征I型（APS1）强调了中央耐受性的重要性，这是一种常染色体隐性单基因自身免疫性综合征，其中受影响的患者会发展出多器官自身免疫性。 APS1中的缺陷基因是自身免疫调节剂（AIRE）基因，该基因负责通过髓质胸腺上皮细胞（MTEC）表达数千种组织限制抗原（TRA）。 MTEC在MHC II类的背景下为开发T细胞的TRA提供了TRA，从而可以删除自动反应性T细胞。虽然已知AIR对TRA基因表达至关重要，但AIRE用来诱导TRA基因的确切机制尚不清楚。对AIRE的作用机理的进一步了解将产生有关APS1发病机理以及其他更常见的自身免疫性疾病的见解，这些疾病最近与AIRE（例如类风湿关节炎）有关。这项职业发展建议有两个主要目标。首先，候选人概述了一项为期5年的职业发展计划，以建立独立的研究计划。该计划的重点包括马克·安德森（Mark Anderson）博士的心态，马克·安德森（Mark Anderson）是一个委员会，该委员会旨在在候选人的进步，教学课程中提供科学和职业建议，会议，以补充当地的科学丰富和网络机会，最后是实验室管理和专业技能的研讨会。其次，候选人概述了一项为期5年的研究策略，以研究与AIRE的行动机理有关的基本问题。最近的研究已经确定了两种新型的AIRE互动蛋白，以前已知与基因表达的表观遗传学有关：激活转录因子7相互作用蛋白（ATF7IP）和甲基CpG结合蛋白1（MBD1）。 AIRE与ATF7IP/MBD1蛋白复合物的相互作用对于TRA基因表达至关重要，并且在最近的自然免疫学论文中发表的数据表明，AIRE结合MBD1在诱导的TRA基因表达中的特异性。此外，与MBD1在TRA基因表达中的作用一致，MBD1 - / - 小鼠会发展自身免疫性。 AIM 1将检查MBD1在免疫耐耐受性中的细胞机制。 AIM 2将询问ATF7IP在TRA基因表达和预防自身免疫性中的体内作用。 AIM 3旨在进一步定义AIRE用来靶向体内TRA基因的分子机制。该候选人是加利福尼亚大学旧金山大学（UCSF）的MSTP毕业生和小儿风湿病学家。尽管候选人具有免疫学背景，但先前使用的先前研究和技术领域与他目前的科学重点相距甚远。因此，他将从提案中概述的结构化心态和培训时期中受益。培训期结束后，候选人将继续在学术医学中心制定一个独立的研究计划，其长期目标是了解自身免疫性疾病的基本机制。 UCSF为培训儿科医师科学家提供了理想的环境。 UCSF儿科部在促进年轻教师的职业发展方面有着悠久的记录。此外，UCSF免疫学计划具有独特的免疫学专业知识广度，许多研究人员是各自领域的领导者。总而言之，该提案将促进候选人的临床和科学作品集的持续发展。提案完成后，候选人可能会为我们对中央耐受性和自身免疫性疾病的理解做出许多原始贡献。候选人还将在制定独立研究计划时竞争进一步的资金机会。