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

项目摘要 这项研究建议的目的是支持Palak Shah，MD，MS发展成为 独立研究人员，并对循环的、无细胞的microRNA进行新的、变革性的探索 (CCF-miR)在心脏移植中的应用循环中的、无细胞的MIR可作为同种异体移植的非侵入性生物标志物 排斥反应和心脏移植物血管病(CAV)是导致心脏发病率和死亡率的两大原因 移植受者。这位候选人沙阿博士展示了他对学术的长期承诺 攻读临床和翻译研究硕士学位。作为初级教员，沙阿博士 早期的工作集中在识别基于血液的生物标记物，以更好地管理患者 晚期心力衰竭、左心室辅助装置(LVAD)和移植后。K23大奖 将扩展基因组分析开发和生物标记物验证方面的初步经验，包括：1)分离 从血液样本中提取CCF-miRs并制备用于下一代测序的生物样品；2)测序 数据比对和序列数据的生物信息学解释；以及3)开发一个临床小组 CCF-miR生物标记物用于检测同种异体移植排斥反应 临床数据。 为实现这些目标，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，正式的课程工作和指导性研究 经验丰富的导师。导师团队包括多位思想领袖，他们具有相关的详细专业知识 对于申请者的职业目标：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)，朱军，博士(RNA测序和生物信息学分析)，汉娜·瓦兰丁，医学博士(心脏 移植和基因组生物标记物)，以及Christopher Defilippi，MD(心血管生物标记物发现 和验证)。本研究的具体目的是：1)确定心脏CCF-miR转录组 移植受者识别区分心脏移植排斥反应的新的miR生物标记物；2)区分 慢性排斥反应的CCF-miR生物标志物表现为心脏移植物血管病变。 之前的基础工作和培训已经使沙阿博士做好了准备，可以成功地实施拟议的 研究，并将他转变为一名独立调查员。预计研究结果将建立一个 CCF-miRs作为同种异体移植排斥和CAV诊断生物标志物的框架。一旦经过临床验证 在未来的多中心研究中，CCF-miRs可用于无创性诊断同种异体移植排斥反应和CAV。 心脏移植患者。

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.