Mechanisms of AIRE SAND-Domain Variants in Autoimmunity

项目摘要/摘要 这项为期五年的辅导性研究职业发展项目的建议重点是研究 AIRE蛋白在致病突变的背景下发挥作用。该提案的重点研究目的是 为了了解AIRE沙区中的一种新突变损害蛋白质的机制 功能。该提案的发展目标是进一步发展申请人理解 基因变异对蛋白质功能的功能影响，最终为研究 基因变异与临床疾病结局直接相关。提案中概述的实验包括 表达载体的遗传操作、蛋白质在细胞系中的表达、蛋白质的各种模式 携带突变小鼠的分离及免疫学特性研究。这些实验将会进行 在皮帕·马拉克医学博士、约翰·卡普尔博士和马克·安德森博士的指导下，领导 在免疫学和生物化学领域。 候选人目前是该司国家犹太人健康中心的儿科学助理教授 过敏和免疫学博士。他的主要兴趣是单基因免疫疾病。他过去的工作涉及 新形式的遗传性初级免疫缺陷的特征，他与多个 杰出的研究人员描述了在他的患者中发现的新的遗传免疫疾病。概述 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 通过尝试通过以下方式了解其确切的分子机制 哪些基于人类的突变会影响AIRE蛋白。该发展计划极大地扩大了 候选人理解基因变异与蛋白质结构和功能的相关性的能力。更多 具体地说，建议的实验和教学工作提供了理解 AIRE蛋白，一种对正常免疫耐受至关重要的蛋白质，他以前在其中发现了 一种新的功能突变。更广泛地说，该项目将通过一组独特的十字架来定位候选人 纪律技能，使他能够过渡到独立，成为一名高效的内科科学家 临床免疫学领域，对免疫耐受机制有特别深入的了解。

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.