Identifying Novel Diagnostics and Mechanisms for Cardiac Allograft Vasculopathy

项目总结/摘要 拟议的K23职业发展奖将使凯文·克莱金博士能够建立一个独立的 在心脏移植物血管病（CAV）的诊断和机制方面具有专业知识的研究生涯。博士 Clerkin是一位临床高级心力衰竭和移植心脏病专家，其长期目标是优化结果 心脏移植受者的CAV。然而，要实现这一目标，还需要进一步的培训。作为 因此，他组建了一个多学科的导师团队，在以下方面具有个人专长：（1）移植心脏病学 (2)移植免疫学（3）临床试验设计和实施（4）多模态心脏成像和（5）研究 传播。职业发展计划包括正式的课程和移植指导会议 免疫学和临床试验设计。此外，它还涉及职业生涯中的活动和指导经验 发展、研究传播和推广。心脏移植是金标准治疗 终末期心力衰竭，每年折磨约25万美国人。鉴于CAV是导致 1/3的移植患者中，有必要提高对CAV的认识和诊断能力。的 这次K23研究培训的主要目标是改进CAV的诊断并确定其机制 激发早期CAV，以便为未来的研究奠定基础，以测试针对该途径的疗法。 该建议包括两个相互关联的研究，以实现这一目标，通过临床和转化 research.首先，我们假设基于生理学的筛查（测量冠状动脉血流量或 冠状动脉血流储备[CFR]）将改善CAV的诊断优于传统的血管造影术。我们也 假设在非侵入性心脏PET扫描上测量的CFR将与使用 在冠状动脉造影期间使用压力导丝，从而允许进行新的主要是非侵入性的筛查 approach.在第二个翻译研究中，我们将利用研究1的CAV表型分析来探索 不确定潜能的克隆造血（CHIP）作为早期CAV的潜在机制。成人CHIP 与动脉粥样硬化的风险增加有关， 趋化因子和细胞因子。虽然目前还不知道它对CAV的影响，但根据我们以前的工作， 我们鉴定了CAV再移植患者冠状动脉周围的巨噬细胞群， 假设CHIP患者发生CAV的风险增加。靶向基因测序将是 对我们生物库中患者的外周血样本进行检测，以检测CHIP的存在 并评估其与早期CAV的关系。这个K23提案将使Clerkin博士能够实现他的目标， 1)改善CAV的诊断，2）确定用于优化CAV相关患者治疗后结果的新靶点， 心脏移植，以及3）促进他发展成为移植领域的独立调查员 心脏病学

PROJECT SUMMARY/ABSTRACT The proposed K23 Career Development Award will enable Dr. Kevin Clerkin to establish an independent research career with expertise in the diagnosis and mechanism of cardiac allograft vasculopathy (CAV). Dr. Clerkin is a clinical advanced heart failure & transplant cardiologist, whose long-term goal is to optimize outcomes of heart transplant recipients with respect to CAV. However, further training is required to achieve that goal. As such, he has assembled a multidisciplinary team of mentors with individual expertise in: (1) transplant cardiology (2) transplant immunology (3) clinical trial design and conduct (4) multimodality cardiac imaging and (5) research dissemination. The career development plan includes formal coursework and mentored meetings in transplant immunology and clinical trial design. Additionally, it involves activities and mentored experiences in career development, research dissemination, and grantsmanship. Heart transplantation is the gold standard treatment for end-stage heart failure, afflicting ~250,000 Americans annually. Given that CAV is the cause of death for up to 1/3rd of transplant patients, it is necessary to improve our understanding and ability to diagnose CAV. The primary objective of this K23 research training is to improve diagnostics for CAV and identify mechanisms instigating early CAV in order to lay the groundwork for future studies to test therapies targeting that pathway. This proposal consists of two interrelated studies to achieve this objective through clinical and translational research. In the first, we hypothesize that physiology based screening (measuring coronary blood flow or coronary flow reserve [CFR]) will improve the diagnosis of CAV over traditional angiography. We also hypothesize that CFR measured on a non-invasive cardiac PET scan will correlate with CFR measured using a pressure wire during coronary angiography, thereby allowing for a new primarily non-invasive screening approach. In the second translational study we will leverage the careful CAV phenotyping of Study 1 to explore clonal hematopoiesis of indeterminate potential (CHIP) as a potential mechanism for early CAV. CHIP in adults has been associated with an increased risk of atherosclerosis, mediated by increased inflammatory macrophage chemokines and cytokines. While presently nothing is known of its impact on CAV, based on our previous work identifying populations of macrophages surrounding coronary arteries of patients retransplanted for CAV, we hypothesize that patients with CHIP will have an increased risk of CAV. Targeted gene sequencing will be performed on peripheral blood samples from patients in our biobank in an effort to detect the presence of CHIP and assess its association with early CAV. This K23 proposal will position Dr. Clerkin to accomplish his goals of 1) improving diagnosis of CAV, 2) identifying a novel target for optimizing CAV related patient outcomes post- heart transplant, and 3) facilitating his development into an independent investigator in the field of transplant cardiology.