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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：PI是儿科移植肾脏科医生，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，成人和儿童肾脏移植衰竭的主要原因。慢性同种异体移植肾病没有有效的治疗，并且在10年内几乎所有功能性肾脏移植中都普遍存在。可以早期检测（且可能可逆的）疾病形式的新型致病生物标志物将提供新的治疗靶标，以改善肾脏移植生存。慢性同种异体移植肾病是一种血管疾病，是由于时间依赖性免疫和非免疫血管损伤引起的，开始了移植后早期。由于减少免疫学的疗法尚未降低慢性同种异体肾病的发生率，因此非免疫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肾移植损伤有助于持续的血管损伤的中心假设，这会导致慢性同种异体移植肾病通过与慢性肾脏病媒体麦芽鼻骨障碍（CKD-MBD）有关的非免疫病原因素（CKD-MBD）。这一假设是由CKD翻译模型中最近的第二个发现（PI的重要贡献）形成的。研究计划是拟议的职业发展计划的一个组成部分，该计划具有以下三个目标：1）成为肾脏移植和移植失败机制的专家，包括长期同种异源性肾病； 2）提高PI对肾脏移植中血管生物学/病理学的了解； 3）成为一名独立的临床研究者，他促进了我们对慢性同种异体肾病中血管损伤的理解，以改善肾脏移植结局。为了实现这些目标，PI将通过完成临床研究硕士学位来接受先进的临床研究培训。 PI将从移植肾脏和血管生物学专家团队中获得出色的心理。拟议的研究和职业发展计划将在伊利诺伊州南部大学（PI的专业之家）和华盛顿大学（WU，他的研究培训和CTSA的家中）支持的卓越培训环境中进行。 AIM 1A/1B将在肾脏移植的横截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）在我们的生物座位上注册。 AIM 2将评估CKD-MBD因子作为肾移植结果的生物标志物，这是对入射肾脏移植受者的前瞻性3年纵向研究（n = 40）。第三个探索性目标将使用对移植血管损伤的AIM 1和2受试者的RNA-SEQ研究来鉴定与移植血管损伤有关的新机械途径。这将有助于PI学习并应用通过WU-CTSA核心获得的新兴基因组技术，以研究他对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提高我们对慢性同种异体肾病中血管损伤的理解，并使他能够过渡到独立的临床研究者。