Coopting epigenetic regulators by Aire to maintain immune tolerance

 描述(由申请人提供)：自身免疫性疾病影响大约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尚不清楚，但被认为是环境和遗传因素共同作用的结果。人类用来预防自身免疫性疾病的一个关键机制是中枢耐受过程，在这个过程中，胸腺中的自我反应性T细胞被删除。自身免疫多腺体综合征I型(APS1)强调了中枢耐受的重要性，APS1是一种常染色体隐性遗传单基因自身免疫综合征，患者发生多器官自身免疫。APS1中的缺陷基因是自身免疫调节基因(AIRE)，它负责髓质胸腺上皮细胞(MTECs)表达数千种组织限制性抗原(Tras)。MTECs在MHC II类的背景下向发育中的T细胞提供转运蛋白，使自身反应性T细胞能够被删除。虽然已知Aire对TRA基因的表达至关重要，但Aire诱导TRA基因表达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APS1的发病机制，以及最近被认为与AIRE有关的其他更常见的自身免疫性疾病，如类风湿性关节炎。这份职业发展提案有两个主要目标。首先，候选人勾勒出一个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Mark Anderson博士的指导，该委员会的结构是在候选人的进步过程中提供科学和职业建议，授课课程，补充当地科学丰富和网络机会的会议，以及最后关于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年的研究战略，以审查与Aire的作用机制相关的基本问题。最近的研究发现了两个新的Aire相互作用蛋白：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蛋白复合体的相互作用对TRA基因的表达至关重要，最近发表在一篇自然免疫学论文中的数据表明，Aire结合MBD1具有诱导TRA基因表达的特异性。此外，与MBD1TRA基因表达中S的作用一致，Mbd1-/-小鼠产生了自身免疫。目的1研究MBD1在免疫耐受中的细胞机制。目的2探讨ATF7ip在体内对TRA基因表达的影响及对自身免疫的预防作用。目的3试图进一步确定Aire在体内靶向TRA基因的分子机制。应聘者是MSTP毕业生，也是加州大学旧金山分校(UCSF)的儿科风湿病专家。尽管候选人有免疫学背景，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组织的指导和培训时期。完成培训后，候选人将继续在学术医学中心开发独立的研究计划，长期目标是了解自身免疫性疾病的潜在机制。加州大学旧金山分校为儿科内科科学家的培训提供了理想的环境。加州大学旧金山分校儿科系在培养年轻教师的职业发展方面有着长期的记录。此外，加州大学旧金山分校的免疫学项目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。总而言之，这项建议将促进候选人的临床和科学组合的持续发展。提案完成后，候选人很可能对我们对中枢耐受和自身免疫性疾病的理解做出了许多原创性的贡献。候选人还将在开发独立研究计划的过程中竞争进一步的资助机会。

 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.