Novel Biomarkers of Angiogenesis and Vascular Injury in Chronic Rejection

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 DESCRIPTION (provided by applicant): The PI is a pediatric transplant nephrologist whose long-term career goal is to elucidate the role of vascular injury in chronic allograft nephropathy, the primary cause of kidney transplant failure in adults and children. Chronic allograft nephropathy has no effective treatment and is prevalent in nearly all functioning kidney transplants within 10 years. Novel pathogenic biomarkers that can detect early (and perhaps reversible) forms of disease will provide new therapeutic targets that are needed to improve kidney transplant survival. Chronic allograft nephropathy is a vascular disease resulting from time-dependent immune and non-immune vascular injury that begins early post-transplant. Since therapies that reduce immune injury have not reduced the incidence of chronic allograft nephropathy, the contributions of non-immune vascular injury need further investigation. The proposed research training plan will investigate the central hypothesis that kidney transplant injury contributes to ongoing vascular injury that leads to chronic allograft nephropathy through non-immune pathogenic factors involved in the chronic kidney disease-mineral bone disorder (CKD-MBD). This hypothesis was formed by recent seminal discoveries (with critical contributions from the PI) in translational models of CKD. The research plan is a component of the proposed career development plan that has the following three goals: 1) to become an expert in kidney transplantation and mechanisms of transplant failure, including chronic allograft nephropathy; 2) to improve the PI's knowledge of vascular biology/pathology in kidney transplantation; 3) to become a productive independent clinical investigator who advances our understanding of vascular injury in chronic allograft nephropathy to improve kidney transplant outcomes. To achieve these goals the PI will receive advanced clinical research training by completing a Master of Science in Clinical Investigation degree. The PI will receive exceptional mentoring from a team of experts in transplant nephrology and vascular biology. The proposed research and career development plans will be carried out in a superior training environment supported by Southern Illinois University (PI's professional home) and Washington University (WU, his research training and CTSA home). Aim 1a/1b will establish and validate CKD-MBD factors as biomarkers of transplant vascular injury in a cross-sectional study of kidney transplant recipients (n=120) enrolled in our biorepository. Aim 2 will evaluate CKD-MBD factors as biomarkers of kidney transplant outcomes in a prospective 3-year longitudinal study of incident kidney transplant recipients (n=40). A third exploratory aim will identify novel mechanistic pathways involved in transplant vascular injury using RNA-seq studies of subjects from aims 1 and 2 with transplant vascular injury. This will help the PI learn and apply emerging genomic technologies, available through the WU-CTSA core, to his studies of transplant vascular injury. The PI expects that completion of the proposed research and career development plans will advance our understanding of vascular injury in chronic allograft nephropathy and enable his transition to an independent clinical investigator.