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

了解 Allo 和自身免疫的界面：血管紧张素 II 1 型受体抗体对儿童肾移植受者的影响

• 批准号: 10176385
• 负责人: Meghan Haley Pearl
• 金额: $ 20.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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/10176385
• 关键词: Acute; Adult; Allografting; Angiotensin Receptor; Angiotensins; Antibodies; Area; Arteritis; Autoantibodies; Autoimmunity; Award; Biometry; Biopsy; Biopsy Specimen; Blood Circulation; Blood specimen; California; Child; Childhood; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Design; Data; Development; Development Plans; Dialysis procedure; Doctor of Philosophy; End stage renal failure; Endothelial Cells; Extracellular Signal Regulated Kinases; Fc Receptor; Fellowship; Foundations; Frequencies; Functional disorder; Funding; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene-Modified; Goals; HLA Antigens; High Prevalence; Hypertension; IL8 gene; Immunofluorescence Immunologic; Immunogenetics; Immunologic Monitoring; Immunologics; Immunology; Inflammatory; Injury; Interleukin-1 beta; Interleukin-6; Isoantibodies; Kidney; Kidney Transplantation; Longitudinal Studies; Los Angeles; Losartan; Master of Science; Measures; Mediating; Mediator of activation protein; Medicine; Mentorship; Molecular; Molecular Profiling; Nephrology; Odds Ratio; Organ Transplantation; Outcome; PECAM1 gene; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Physicians; Pilot Projects; Population; Process; Publishing; Quality of life; Receptor, Angiotensin, Type 1; Renal function; Research; Role; Sampling; Scientist; Serum; Severities; Signal Pathway; Signal Transduction; Stains; Study models; TNF gene; Therapeutic Agents; Thromboplastin; Time; Tissues; Training; Training Programs; Transplant Recipients; Transplantation; Universities; Vulnerable Populations; Work; antibody test; antibody-mediated rejection; career; career development; cohort; cytokine; donor-specific antibody; education planning; improved; in vivo; kidney allograft; laboratory experience; medical schools; novel strategies; novel therapeutics; pediatric patients; post-transplant; professor; renal damage; risk stratification; skills; study population; success; synergism; targeted treatment; transcriptome; treatment choice; vascular inflammation; vascular injury

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.

项目摘要/摘要 该提案概述了一项为期5年的职业发展计划，为医学博士梅根（Meghan Pearl） 加州大学洛杉矶分校的大卫·格芬医学院的小儿肾脏病科 （UCLA）。 Pearl博士最近在加州大学洛杉矶分校完成了她的儿科肾脏学研究金，并具有很高的动力 开始从事学术医学的职业。她最近获得了临床科学硕士学位 研究（2018年6月授予的学位）将为她提议的额外提供理想的基础 训练。她将从Elaine F Reed的超级思想中受益，博士，世界知名领导人 免疫原性和移植免疫学。在里德博士的指导下，珀尔博士将完成必不可少的 培训目标将为成功实现她的长期目标提供基础 独立的临床研究者。她的培训计划的核心将是1）完成基本培训 通过正式的课程和实验室经验，2）扩大她的统计数据 通过在计算生物统计学方面进行深入培训的技能，以及3）获得临床领域的高级专业知识 试验设计，行为和管理。该教育计划将导致获得必要的技能 成为一名独立的身体科学家，并成功地争夺R01资金。 Pearl博士的培训目标将与她的拟议研究无缝集成，该研究的重点是 血管紧张素II型1型受体抗体（AT1R-AB）在小儿肾脏中的临床影响和病理生理学 移植接受者（KTRS）。 Pearl博士在她的试点研究中发现，AT1R-移植后的发展 AB是一种自身抗体，在儿科与成人KTR中更为普遍，并且与同种异体移植有关 移植后最初两年的肾功能损失和下降。这项研究的总体目标是 在移植后的头5年中，鉴定小儿KTR中AT1R-AB介导的同种异体移植损伤的模式。 我们假设AT1R-AB介导同种异体移植中的血管感染导致肾脏下降 移植后最初5年的功能和分组损失。我们进一步假设AT1R-AB激活 异源中内皮细胞，导致与合金损伤相关的独特分子特征和 损失。这项研究不仅会丰富我们对AT1R-AB发病机理的理解，而且还可以作为模型 非HLA抗体介导的合物损伤的研究 - 该地区目前非常了解。 儿科KTR将从给定的工作中受益最大的1）AT1R-AB的高频 人口和2）由于需要重复而导致的免疫并发症的脆弱性 一生中的移植。这项研究将有助于确定AT1R-AB测试在免疫学中的实用性 KTR的风险分层以及积极的，有针对性治疗对肾脏同种异体生存的潜在影响， 因此，患者的生存和生活质量。