Mechanisms of AIRE SAND-Domain Variants in Autoimmunity

AIRE 沙域变异体在自身免疫中的机制

• 批准号: 10191520
• 负责人: Jordan Abbott
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191520
• 关键词: Affect; American; Animal Model; Animals; Antibodies; Antigens; Arginine; Autoantibodies; Autoimmune Diseases; Autoimmunity; Award; Basic Science; Behavior; Biochemistry; Cancer Burden; Cause of Death; Cell Line; Cell Nucleus; Charge; Clinical; Clinical Immunology; Data; Development; Development Plans; Disease Outcome; Doctor of Medicine; Doctor of Philosophy; Economic Burden; Educational Curriculum; Ensure; Ethnic Origin; Failure; Fostering; Foundations; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic Variation; Genomics; Goals; Health; Human; Hypersensitivity; Immune; Immune System Diseases; Immune Tolerance; Immune system; Immunologics; Immunology; Impairment; Infiltration; Insulin-Dependent Diabetes Mellitus; Laboratories; Lymphocyte; Measures; Mediator of activation protein; Mentors; Mentorship; Missense Mutation; Molecular; Molecular Biology; Mus; Mutation; Organ; Parents; Pathogenicity; Patients; Pediatrics; Peripheral; Phenotype; Physicians; Plasmids; Play; Positioning Attribute; Preventive Intervention; Production; Protein Biochemistry; Proteins; Reporting; Research; Research Personnel; Rheumatoid Arthritis; Role; Scientist; Screening procedure; Series; Side; Structure of thymic medulla; Syndrome; System; T-Lymphocyte; Thymic epithelial cell; Thymus Gland; Tissues; Training; Transcriptional Activation; Translational Research; United States; Variant; Woman; Work; autoreactive T cell; base; career development; central tolerance; clinical predictors; congenital immunodeficiency; cost; disease-causing mutation; experience; experimental study; expression vector; follower of religion Jewish; genetic manipulation; genetic variant; human subject; in vivo; insight; interest; loss of function; mouse model; mutant; novel; professor; protein aggregation; protein expression; protein function; protein protein interaction; protein structure function; skills; tool; transcription factor

Project Summary/Abstract This proposal for a five-year mentored research career development project focuses on the study of AIRE protein function in the context of disease-causing mutations. The focused research aim of the proposal is to understand the mechanism by which a novel mutation within the SAND domain of AIRE impairs the protein’s function. The developmental aim of the proposal is further develop the applicant’s capability to understand the functional impact of genetic variation on protein function, ultimately providing the groundwork for research that directly ties genetic variation to clinical disease outcomes. The experiments outlined in the proposal include genetic manipulations of expression vectors, expression of proteins in cell lines, various modes of protein isolation, and immunologic characterization of mutant carrying mice. These experiments will be carried out under the mentorship of Pippa Marrack, M.D., John Kappler, Ph.D., and Mark Anderson, M.D., Ph.D., leaders in the fields of immunology and biochemistry. The candidate is currently an Assistant Professor of Pediatrics at National Jewish Health in the Division of Allergy and Immunology. His primary interest is in monogenetic immune disease. His past work has involved the characterization of novel forms of genetic primary immunodeficiency, and he has collaborated with multiple prominent researchers to characterize novel genetic immune disorders identified in his patients. The outlined proposal builds on the candidate’s previous research and clinical experience in the genetic cause of immune deficiency, dysregulation, and dysfunction by attempting to understand the precise molecular mechanism by which human-based mutations affect the AIRE protein. The development plan dramatically expands the candidate’s capability to understand the relevance of genetic variants to protein structure and function. More specifically, the proposed experiments and didactic work provide the opportunity to understand the function of the AIRE protein, a protein that is essential for normal immune tolerance, and in which he previously identified a novel functional mutation. More generally, the project will position the candidate with a unique set of cross disciplinary skills that will enable him to transition to independence as a highly productive physician scientist in the field of clinical immunology with particular insight into mechanisms of immune tolerance.

项目总结/摘要 这项为期五年的研究职业发展项目的建议侧重于研究 AIRE蛋白在致病突变背景下的功能本方案的重点研究目标是 为了了解AIRE的SAND结构域中的新突变损害蛋白质功能的机制， 功能该提案的发展目标是进一步发展申请人理解 遗传变异对蛋白质功能的功能影响，最终为研究提供基础， 将遗传变异与临床疾病结果直接联系起来。提案中概述的实验包括 表达载体的遗传操作，细胞系中蛋白质的表达，蛋白质的各种模式 携带突变体小鼠的分离和免疫学表征。这些实验将在 在医学博士皮帕·马拉克的指导下，John Kappler博士，和医学博士马克安德森，哲学博士、领导人 在免疫学和生物化学领域。 候选人目前是儿科助理教授在国家犹太健康在该司 过敏和免疫学他的主要兴趣是单基因免疫疾病。他过去的工作涉及 新形式的遗传原发性免疫缺陷的表征，他与多个 杰出的研究人员来描述他的病人中发现的新型遗传免疫疾病。概述的 建议建立在候选人以前的研究和临床经验的遗传原因的免疫 缺乏，失调和功能障碍，试图了解精确的分子机制， 哪些人类基因突变会影响AIRE蛋白发展计划大大扩大了 候选人理解遗传变异与蛋白质结构和功能相关性的能力。更 具体而言，拟议的实验和教学工作提供了机会，了解的功能， AIRE蛋白，一种对正常免疫耐受至关重要的蛋白质，他先前在其中鉴定出 一种新的功能突变更一般地说，该项目将定位候选人与一套独特的交叉 学科技能，这将使他能够过渡到独立作为一个高产的医生科学家， 临床免疫学领域，特别是对免疫耐受机制的深入了解。