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: 10434064
• 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/10434064
• 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; 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; Testing; Therapeutic Agents; Thromboplastin; Time; Tissues; Training; Training Programs; Transplant Recipients; Transplantation; Transplantation Immunology; Universities; Vulnerable Populations; Work; 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.

项目概要/摘要 该提案概述了医学博士梅根·珀尔 (Meghan Pearl) 的 5 年职业发展计划，她是该学院的助理教授。 加州大学洛杉矶分校大卫格芬医学院儿科肾脏病科 （加州大学洛杉矶分校）Pearl 博士最近完成了加州大学洛杉矶分校儿科肾脏病学的研究，并且充满动力。 她最近获得了临床理学硕士学位，开始从事学术医学事业。 研究（2018 年 6 月授予学位）将为她提出的额外建议提供理想的基础 她将受益于世界知名领导者 Elaine F Reed 博士的优质指导。 在里德博士的指导下，珀尔博士将完成免疫遗传学和移植免疫学的基本工作。 培训目标将为她成功实现长期目标奠定基础 一名独立的临床研究者。她的培训计划的核心是 1) 完成必要的培训。 通过正式课程和实验室经验在移植免疫学方面取得了进展，2）扩大了她的统计数据 通过计算生物统计学强化培训获得技能，以及 3) 获得临床方面的高级专业知识 该教育计划将导致患者获得必要的技能。 成为移植领域的独立医师科学家并成功竞争 R01 资助。 Pearl 博士的培训目标将与她提出的研究无缝结合，该研究的重点是 血管紧张素 II 1 型受体抗体 (AT1R-Ab) 对小儿肾脏的临床影响和病理生理学 Pearl 博士在她的初步研究中发现，AT1R 的移植后发育- Ab 是一种自身抗体，在儿童 KTR 中比成人 KTR 中更为常见，并且与同种异体移植相关 移植后头 2 年内肾功能丧失和衰退1 本研究的首要目标是。 确定移植后 5 年内 AT1R-Ab 介导的儿童 KTR 中同种异体移植物损伤的模式。 我们发现 AT1R-Ab 介导同种异体移植物中的血管炎症，导致肾功能下降 我们进一步研究了 AT1R-Ab 的激活情况。 同种异体移植物内的内皮细胞产生与同种异体移植物损伤相关的独特分子特征 这项研究不仅将丰富我们对 AT1R-Ab 发病机制的理解，而且可以作为模型。 对非 HLA 抗体介导的同种异体移植物损伤的研究——目前对该领域知之甚少。 鉴于 1) AT1R-Ab 在该研究中的高频率，儿科 KTR 将从这项工作中受益最多 人群和 2) 由于需要重复治疗，他们容易出现免疫并发症 这项研究将有助于确定 AT1R-Ab 检测在免疫学中的效用。 KTR 的风险分层以及主动、有针对性的治疗对肾同种异体移植物存活的潜在影响， 因此，患者的生存率和生活质量。