Understanding the Interface of Allo and Auto-Immunity: The Impact of Angiotensin II Type 1 Receptor Antibodies in Pediatric Kidney Transplant Recipients

项目摘要/摘要 这份提案概述了梅根·珀尔医学博士的5年职业发展计划。 加州大学洛杉矶分校大卫·格芬医学院儿科肾病 (加州大学洛杉矶分校)。珀尔医生最近完成了她在加州大学洛杉矶分校的儿科肾病研究，她的积极性很高 开始在学术医学领域的职业生涯。她最近获得了临床理学硕士学位 研究(2018年6月授予学位)，这将为她提议的额外 训练。她将受益于伊莱恩·F·里德博士的卓越指导，伊莱恩·里德博士是世界知名的 免疫遗传学和移植免疫学。在里德博士的指导下，珀尔博士将完成基本 培训目标，这将为成功实现她成为 一名独立的临床调查员。她的培训计划的核心将是完成基本培训 在移植免疫学方面通过正规的课程和实验室经验，2)扩展了她的统计学 通过计算生物统计学的强化培训获得技能，以及3)获得临床方面的高级专业知识 试验设计、实施和管理。这项教育计划将导致获得必要的技能。 成为移植领域的独立内科科学家，并成功争取R01资金。 珀尔博士的培训目标将与她提出的研究无缝结合，这项研究的重点是 血管紧张素II 1型受体抗体(AT1R-Ab)在儿童肾脏的临床意义及病理生理意义 移植受者(KPR)。在她的先导研究中，珀尔博士发现，移植后AT1R的发育- AB是一种自身抗体，在儿童KDR中比成人KDR中更为普遍，并与同种异体移植有关。 移植后2年内肾功能的丧失和下降1。这项研究的首要目标是 目的：确定AT1R-Ab介导的同种异体肾移植后5年内儿童移植物的损伤模式。 我们假设AT1R-Ab介导同种异体移植肾血管炎症导致肾功能下降 移植后前5年的功能和同种异体移植物的丢失。我们进一步假设AT1R-Ab激活 同种异体移植物内的内皮细胞导致与同种异体移植物损伤相关的独特分子特征 损失。这一研究不仅将丰富我们对AT1R-Ab发病机制的认识，而且还将为临床提供一个模型。 非人类白细胞抗原抗体介导的同种异体移植物损伤的研究--这一领域目前知之甚少。 儿科KDR将从这项工作中受益最大，因为1)AT1R-Ab在 人口和2)由于需要反复接种疫苗而易患免疫并发症 在他们的一生中进行移植。这项研究将有助于确定AT1R-Ab检测在免疫学中的应用 KTRs的风险分层和积极的、有针对性的治疗对移植肾存活的潜在影响 因此，患者的生存和生活质量。

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year career development plan for Meghan Pearl, MD, an Assistant Professor in the Division of Pediatric Nephrology at the David Geffen School of Medicine, University of California, Los Angeles (UCLA). Dr. Pearl recently completed her fellowship in Pediatric Nephrology at UCLA and is highly motivated to be starting a career in academic medicine. She has recently obtained a Master of Science in Clinical Research (degree awarded June 2018) which will provide the ideal foundation for her proposed additional training. She will benefit from the superior mentorship of Elaine F Reed, PhD, a world renowned leader in Immunogenetics and Transplant Immunology. Under Dr. Reed’s guidance, Dr. Pearl will complete essential training objectives which will provide the groundwork for success in achieving her long term goal of becoming an independent clinical investigator. At the core of her training program will be 1) completing essential training in transplant immunology through formal coursework and laboratory experience, 2) expanding her statistical skills through intensive training in computational biostatistics, and 3) acquiring advanced expertise in clinical trial design, conduct, and management. This education plan will result in the acquisition of the necessary skills to become an independent physician scientist in transplantation and successfully compete for R01 funding. Dr. Pearl’s training objectives will be seamlessly integrated with her proposed research, which is focused on the clinical impact and pathophysiology of angiotensin II type 1 receptor antibody (AT1R-Ab) in pediatric kidney transplant recipients (KTRs). In her pilot study, Dr. Pearl found that the post-transplant development of AT1R- Ab, an autoantibody, is significantly more prevalent in pediatric vs. adult KTRs and is associated with allograft loss and decline in renal function in the first 2 years post-transplant1. The overarching goal of this research is to identify patterns of AT1R-Ab mediated allograft injury in pediatric KTRs in the first 5 years post-transplant. We hypothesize that AT1R-Ab mediates vascular inflammation in the allograft leading to decline in renal function and allograft loss in the first 5 years post-transplant. We further hypothesize that AT1R-Ab activates endothelial cells within the allograft resulting in unique molecular signatures associated with allograft injury and loss. This study will not only enrich our understanding of AT1R-Ab pathogenesis, but also serve as a model for the study of non-HLA antibody mediated allograft injury – an area that is currently very poorly understood. Pediatric KTRs will have the most to benefit from this work given 1) the high frequency of AT1R-Ab in this population and 2) their vulnerability to immunologic complications as a result of the need for repeated transplantation over their lifetimes. This study will help determine the utility of AT1R-Ab testing in immunologic risk stratification of KTRs and the potential impact of proactive, targeted treatment on renal allograft survival, and therefore, patient survival and quality of life.