Novel Biomarkers of Angiogenesis and Vascular Injury in Chronic Rejection

 描述（由申请人提供）：PI是一名儿科移植肾病学家，其长期职业目标是阐明血管损伤在慢性移植物肾病中的作用， 成人和儿童肾移植失败的主要原因。慢性移植物肾病没有有效的治疗方法，并且在10年内几乎所有功能正常的肾移植中普遍存在。可以检测早期（可能可逆）疾病形式的新型病原性生物标志物将提供改善肾移植存活率所需的新治疗靶点。慢性移植物肾病是一种由时间依赖性免疫和非免疫性血管损伤引起的血管疾病，发生于移植后早期。由于减少免疫损伤的治疗并没有降低慢性移植肾肾病的发生率，非免疫性血管损伤的作用需要进一步研究。拟议的研究培训计划将调查中心假设，即肾移植损伤有助于持续的血管损伤，通过参与慢性肾脏疾病-矿物质骨疾病（CKD-MBD）的非免疫致病因素导致慢性移植物肾病。这一假设是由CKD转化模型的最新开创性发现（PI的关键贡献）形成的。该研究计划是拟议职业发展计划的组成部分，具有以下三个目标：1）成为肾移植和移植失败机制（包括慢性移植物肾病）方面的专家; 2）提高PI对肾移植中血管生物学/病理学的知识; 3）成为一名富有成效的独立临床研究者，促进我们对慢性移植物肾病血管损伤的理解，以改善肾移植结果。为了实现这些目标，PI将通过完成临床研究硕士学位接受高级临床研究培训。PI将接受移植肾脏学和血管生物学专家团队的特殊指导。拟议的研究和职业发展计划将在南伊利诺伊大学（PI的专业之家）和华盛顿大学（WU，他的研究培训和CTSA之家）支持的上级培训环境中进行。目的1a/1b将在肾移植的横断面研究中建立和验证CKD-MBD因子作为移植血管损伤的生物标志物 接受者（n=120）在我们的生物储存库登记。目的2将在一项对偶发性肾移植受者（n=40）进行的前瞻性3年纵向研究中评价CKD-MBD因素作为肾移植结局的生物标志物。第三个探索性目标将使用目标1和目标2的移植血管损伤受试者的RNA-seq研究来确定涉及移植血管损伤的新机制途径。这将有助于PI学习和应用新兴的基因组技术，通过WU-CTSA核心，他的移植血管损伤的研究。PI预计，完成拟定的研究和职业发展计划将促进我们对慢性移植物肾病血管损伤的理解，并使其能够过渡到独立的临床研究者。

 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.