Novel Biomarkers of Angiogenesis and Vascular Injury in Chronic Rejection

慢性排斥反应中血管生成和血管损伤的新型生物标志物

• 批准号: 9143101
• 负责人: Michael Edward Seifert
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143101
• 关键词: Acute; Adult; Affect; Biological Markers; Biology; Biopsy; Blinded; Blood; Blood Vessels; Bone Diseases; Child; Childhood; Chronic; Chronic Kidney Failure; Chronic rejection of renal transplant; Clinical; Clinical Investigator; Clinical Research; Consensus; Creatinine; Cross-Sectional Studies; Development Plans; Diagnostic; Diagnostic Procedure; Diagnostic tests; Dialysis procedure; Disease; Early Diagnosis; Enrollment; Environment; Failure; Future; Genomic medicine; Genomics; Goals; Health; Health Care Costs; Home environment; Human; Illinois; Immune; Immunosuppression; Incidence; Injury; Injury to Kidney; Investigation; Kidney; Kidney Transplantation; Knowledge; Learning; Longitudinal Studies; Master of Science; Mentors; Minerals; Modeling; Nephrology; Outcome; Pathogenesis; Pathology; Pathway interactions; Plasma; Preventive; Process; Production; Prospective Studies; Proteins; Renal function; Research; Research Design; Research Training; Role; Sampling; Seminal; Severities; Source; Study Subject; Technology; Time; Training; Transplant Recipients; Transplantation; Trees; Universities; Urine; Validation; Vascular Diseases; Washington; angiogenesis; base; biobank; career; career development; clinical investigation; differential expression; effective therapy; fibroblast growth factor 23; hands-on learning; high risk; improved; injured; injury and repair; insight; kidney vascular structure; loss of function; model design; mortality; new therapeutic target; novel; novel marker; predictive marker; prospective; research and development; research study; skills; targeted treatment; transcriptome sequencing; translational study; treatment strategy; vascular factor

 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.

 描述（由申请人提供）：PI 是一名儿科移植肾病专家，其长期职业目标是阐明血管损伤在慢性同种异体移植肾病中的作用， 成人和儿童肾移植失败的主要原因。慢性同种异体移植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都普遍存在。能够检测早期（也许是可逆）疾病形式的新型致病生物标志物将提供提高肾移植存活率所需的新治疗靶点。慢性同种异体移植肾病是一种血管疾病，由移植后早期开始的时间依赖性免疫和非免疫血管损伤引起。由于减少免疫损伤的治疗并没有降低慢性同种异体移植肾病的发病率，因此非免疫性血管损伤的贡献需要进一步研究。拟议的研究培训计划将调查一个中心假设，即肾移植损伤会导致持续的血管损伤，从而通过参与慢性肾病-矿物质骨病（CKD-MBD）的非免疫致病因素导致慢性同种异体移植肾病。这一假设是由最近 CKD 转化模型中的开创性发现（PI 的关键贡献）形成的。该研究计划是拟议职业发展计划的一部分，该计划具有以下三个目标：1）成为肾移植和移植失败机制（包括慢性同种异体移植肾病）方面的专家； 2）提高PI对肾移植血管生物学/病理学的了解； 3）成为一名富有成效的独立临床研究者，增进我们对慢性同种异体移植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理学硕士学位来接受高级临床研究培训。 PI 将接受移植肾病学和血管生物学专家团队的卓越指导。拟议的研究和职业发展计划将在南伊利诺伊大学（PI 的专业所在地）和华盛顿大学（WU，他的研究培训和 CTSA 所在地）支持的优越培训环境中进行。目标 1a/1b 将在肾移植横断面研究中建立并验证 CKD-MBD 因子作为移植血管损伤的生物标志物 接受者 (n=120) 在我们的生物存储库中注册。目标 2 将在一项针对肾移植受者 (n=40) 的前瞻性 3 年纵向研究中评估 CKD-MBD 因素作为肾移植结果的生物标志物。第三个探索性目标将通过对目标 1 和 2 的移植血管损伤受试者进行 RNA-seq 研究，确定参与移植血管损伤的新机制途径。这将帮助 PI 学习并将通过 WU-CTSA 核心提供的新兴基因组技术应用于移植血管损伤的研究。 PI 预计，拟议的研究和职业发展计划的完成将增进我们对慢性同种异体移植肾病血管损伤的理解，并使他能够转变为独立的临床研究者。