MicroRNA Biomarkers of Allograft Rejection and Cardiac Allograft Vasculopathy in Cardiac Transplantation

心脏移植中同种异体移植排斥和心脏同种异体移植血管病变的 MicroRNA 生物标志物

• 批准号: 10446991
• 负责人: Palak Shah
• 金额: $ 18.58万
• 依托单位: INOVA HEALTH CARE SERVICES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446991
• 关键词: 3' Untranslated Regions; Accounting; Acute; Adverse event; Angiography; Bioinformatics; Biological Assay; Biological Markers; Biometry; Biopsy; Blood; Blood Tests; Blood specimen; Bronchiolitis Obliterans; Cardiovascular system; Cells; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Coronary; Coronary Arteriosclerosis; DNA; Data; Development; Development Plans; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Faculty; Funding; Future; Genomics; Goals; Graft Rejection; Heart Transplantation; Heart failure; Human; Incidence; Infrastructure; K-Series Research Career Programs; Lung Transplantation; Malignant Neoplasms; Mediating; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Messenger RNA; MicroRNAs; Monitor; Morbidity - disease rate; Multicenter Studies; Multicenter Trials; Myocardial tissue; Necrosis; Nucleotides; Outcome; Patients; Plasma; Preparation; Procedures; RNA Binding; Research; Research Personnel; Research Proposals; Risk; Risk Factors; Role; Solid; Specimen; Supervision; Syndrome; T-Lymphocyte; Training; Transcript; Translational Research; Translations; Transplant Recipients; Transplantation; Untranslated RNA; Validation; Vascular Diseases; Work; accurate diagnosis; allograft rejection; antibody-mediated rejection; assay development; base; biobank; biomarker discovery; biomarker panel; biomarker validation; blood-based biomarker; career; career development; circulating microRNA; comorbidity; cost; diagnostic biomarker; differential expression; experience; genomic biomarker; graft dysfunction; heart allograft; in-vitro diagnostics; indexing; left ventricular assist device; member; microRNA biomarkers; mortality; next generation sequencing; noninvasive diagnosis; novel; organ transplant recipient; post-transplant; transcriptome; transcriptome sequencing; transcriptomics; trial design

Project Summary This purpose of this research proposal is to support the development of Palak Shah, MD, MS into an independent investigator, and to conduct novel, transformative explorations of circulating, cell-free microRNAs (ccf-miR) in heart transplantation. Circulating, cell-free miRs may serve as non-invasive biomarkers of allograft rejection and cardiac allograft vasculopathy (CAV), two leading causes of morbidity and mortality in heart transplant recipients. The candidate, Dr. Shah, has demonstrated his long-standing commitment to academic medicine by pursuing a Masters in Clinical and Translational Research. As a junior faculty member, Dr. Shah’s early work has focused on the identification of blood-based biomarkers to better manage patients with advanced heart failure, left ventricular assist devices (LVADs), and following transplantation. The K23 award will extend initial experiences in genomic assay development and biomarker validation to include: 1) isolation of ccf-miRs from blood samples and preparation of biospecimens for next-generation sequencing; 2) sequence data alignment and bioinformatic interpretation of sequence data; and 3) the development of a clinical panel of ccf-miR biomarkers to detect allograft rejection using biostatistical analyses that combine transcriptomic and clinical data. To accomplish these goals, a comprehensive career development plan has been formulated that includes both formal coursework and mentored research under the close supervision and guidance of a senior team of experienced mentors. The mentorship team includes multiple thought-leaders with detailed expertise relevant to the career goals of the applicant: Christopher O’Connor, MD (clinical validation of heart failure biomarkers and trial design), Jun Zhu, PhD (RNA-sequencing and bioinformatic analyses), Hannah Valantine, MD (cardiac transplantation and genomic biomarkers), and Christopher deFilippi, MD (cardiovascular biomarker discovery and validation). The specific aims of the research are to 1) Determine the ccf-miR transcriptome of cardiac transplant recipients to identify novel miR biomarkers that distinguish cardiac allograft rejection; 2) Distinguish ccf-miR biomarkers of chronic rejection manifest as cardiac allograft vasculopathy. Previous groundwork and training have prepared Dr. Shah to successfully undertake the proposed research, and to transition him into an independent investigator. The study results are expected to establish a framework for using ccf-miRs as diagnostic biomarkers of allograft rejection and CAV. Once clinically validated in a future multicenter study, ccf-miRs can be used to non-invasively diagnose allograft rejection and CAV in heart transplant patients.

项目概要 本研究计划的目的是支持 Palak Shah（医学博士、理学硕士）发展成为一名 独立研究者，对循环、无细胞 microRNA 进行新颖、变革性的探索 (ccf-miR) 在心脏移植中的循环、无细胞 miR 可作为同种异体移植物的非侵入性生物标志物。 排斥反应和心脏同种异体移植血管病（CAV）是心脏发病和死亡的两个主要原因 移植接受者沙阿博士表现出了他对学术的长期承诺。 作为初级教员，Shah 博士攻读临床和转化研究硕士学位。 早期工作重点是识别血液生物标志物，以更好地管理患有以下疾病的患者 晚期心力衰竭、左心室辅助装置 (LVAD) 和移植后的 K23 奖。 将扩展基因组检测开发和生物标志物验证方面的初步经验，包括：1) 分离 从血液样本中提取 ccf-miR 并制备用于下一代测序的生物样本；2) 序列 序列数据的数据比对和生物信息学解释；以及 3) 临床小组的开发 ccf-miR 生物标志物使用结合转录组学和 临床数据。 为了实现这些目标，我们制定了全面的职业发展计划，其中包括 在高级团队的密切监督和指导下，进行正式的课程作业和指导研究 经验丰富的导师团队包括多名具有相关专业知识的思想领袖。 申请人的职业目标：Christopher O’Connor，医学博士（心力衰竭生物标志物的临床验证 和试验设计）、Jun Zhu 博士（RNA 测序和生物信息学分析）、Hannah Valantine 医学博士（心脏 移植和基因组生物标志物）和 Christopher deFilippi，医学博士（心血管生物标志物发现） 研究的具体目的是1）确定心脏的ccf-miR转录组。 移植受者识别区分心脏同种异体移植排斥的新型 miR 生物标志物； 慢性排斥反应的 ccf-miR 生物标志物表现为心脏同种异体移植血管病变。 之前的基础工作和培训已为 Shah 博士成功开展拟议的项目做好了准备 研究，并将他转变为一名独立研究者。研究结果预计将建立一个 一旦经过临床验证，使用 ccf-miR 作为同种异体移植排斥和 CAV 的诊断生物标志物的框架。 在未来的多中心研究中，ccf-miR 可用于非侵入性诊断同种异体移植排斥和 CAV 心脏移植患者