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Mechanisms of AIRE SAND-Domain Variants in Autoimmunity

AIRE 沙域变异体在自身免疫中的机制

基本信息

批准号：
10443782
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
项目类别：
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/10443782
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 Persons 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

项目摘要

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.

项目概要/摘要这项为期五年的指导研究职业发展项目的提案重点研究 AIRE 蛋白在致病突变中发挥作用。该提案的重点研究目标是了解 AIRE SAND 结构域内的新突变损害该蛋白质的机制功能。该提案的发展目标是进一步培养申请人理解遗传变异对蛋白质功能的功能影响，最终为以下研究提供基础：遗传变异与临床疾病结果直接相关。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的小鼠的分离和免疫学特征。这些实验将进行在皮帕·马拉克 (Pippa Marrack) 医学博士、约翰·卡普勒 (John Kappler) 博士和马克·安德森 (Mark Anderson) 医学博士、博士等领导者的指导下在免疫学和生物化学领域。该候选人目前是国家犹太健康部门的儿科助理教授过敏和免疫学。他的主要兴趣是单基因免疫疾病。他过去的工作涉及遗传原发性免疫缺陷的新形式的特征，他与多个合作杰出的研究人员描述了在他的患者中发现的新型遗传免疫疾病的特征。概述的该提案建立在候选人之前在免疫遗传原因方面的研究和临床经验的基础上通过尝试了解精确的分子机制来发现缺陷、失调和功能障碍哪些人类突变会影响 AIRE 蛋白。该发展计划极大地扩展了候选人理解遗传变异与蛋白质结构和功能的相关性的能力。更多的具体来说，拟议的实验和教学工作提供了了解功能的机会 AIRE 蛋白，一种对于正常免疫耐受至关重要的蛋白，他之前在其中发现了一种新的功能突变。更一般地说，该项目将为候选人提供一组独特的交叉学科技能将使他能够过渡到独立，成为一名高产的医师科学家临床免疫学领域，特别深入了解免疫耐受机制。