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: 10226374
• 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/10226374
• 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; Intervention; 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; Prevention; 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.

项目摘要/摘要 这项为期五年的研究职业发展项目的提案重点是 在引起疾病的突变的背景下，AIR蛋白的功能是该提案的重点研究目的 了解AIRE的沙域中的新型突变会损害蛋白质的机制 功能。 遗传变异对蛋白质功能的功能影响，最终为研究提供了基础。 将遗传变异与临床疾病结局联系起来。 表达载体的遗传操纵，蛋白质在细胞系中的表达，各种蛋白质模式 携带小鼠的突变体的隔离和免疫学表征。 在医学博士Pippa Marrack的指导下，John Kappler博士和Mark Anderson，M.D。 在免疫学和生物化学领域。 该候选人目前是该部门国家犹太人健康的儿科助理教授 他的过敏和无限症是他过去的工作涉及的。 遗传原发性免疫缺陷的新型形式的表征，并与多个合作 著名的研究人员表征了他的患者鉴定的新型遗传疾病。 提案基于候选人在免疫遗传原因的先前研究和临床经验的基础上 试图通过试图忍受精确分子机械的缺乏，失调和功能障碍 哪些基于人类的突变会影响AIR蛋白。 候选人了解遗传变异与蛋白质结构和功能的相关性的能力。 具体而言，支撑的经验和教学工作为功能提供了统一性 Aire蛋白，一种对正常Imune耐受性至关重要的蛋白质，我先前鉴定出来 一个新颖的功能性跨力，该项目具有独特的交叉 纪律技能将使他能够作为高产的医师科学家过渡到独立性 临床免疫学领域，特别深入了解免疫耐受性机制。