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.
Kidney transplantation is the treatment of choice for both adults and children with severe chronic kidney disease because it significantly improves both quality of life and patient survival. Antibody mediated rejection is the most significant barrier to long-term kidney transplant survival, and though the role of Human Leukocyte Antigen (HLA) donor specific antibodies has been well described in this process, the impact of non-HLA autoantibodies remains poorly understood. This work will help elucidate the clinical impact, allograft pathology, and patterns of allograft injury associated with the Angiotensin II Type 1 Receptor Antibody (AT1R-Ab) (a non- HLA antibody) in children, thus identifying novel strategies to improve immune monitoring and allograft survival that will not only benefit the entire kidney transplant population, but be of particular importance to pediatric patients who are most vulnerable to immunologic complications.
