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

项目摘要 本研究提案的目的是支持Palak Shah，MD，MS发展成为一个 独立的研究者，并进行新的，变革性的探索循环，无细胞的microRNA （ccf-miR）在心脏移植中的作用。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 排斥反应和心脏移植物血管病（CAV）是心脏移植术后发病和死亡的两大主要原因， 移植接受者候选人Shah博士证明了他长期致力于学术研究， 通过攻读临床和转化研究硕士学位。作为一名初级教员，沙阿博士 早期的工作集中在识别基于血液的生物标志物，以更好地管理患有 晚期心力衰竭、左心室辅助装置（LVAD）和移植后。K23奖 将扩展基因组检测开发和生物标志物验证的初步经验，包括：1）分离 来自血液样品的ccf-miR和用于下一代测序的生物样本的制备; 2）测序 序列数据的数据比对和生物信息学解释;和3）开发临床面板， 使用结合了联合收割机转录组学和 临床数据。 为实现这些目标，已制定了一项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， 经验丰富的导师。导师团队包括多位具有相关详细专业知识的思想领袖 申请人的职业目标：Christopher奥康纳，医学博士（心力衰竭生物标志物的临床验证 Jun Zhu，PhD（RNA测序和生物信息学分析），Hannah Valantine，MD（心脏 和Christopher deFilippi，MD（心血管生物标志物发现 验证）。本研究的具体目的是：1）确定心肌细胞中ccf-miR的转录组， 移植受者以鉴定区分心脏同种异体移植物排斥的新的miR生物标志物; 2）区分 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物血管病变。 先前的基础工作和培训使Shah博士能够成功地开展拟议的 研究，并将他转变为独立调查员。研究结果预计将建立一个 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。一旦临床验证 在未来的多中心研究中，ccf-miRs可用于非侵入性诊断同种异体移植排斥反应和冠状动脉萎缩 心脏移植病人

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.