Identifying Novel Diagnostics and Mechanisms for Cardiac Allograft Vasculopathy

确定心脏同种异体移植血管病的新诊断方法和机制

• 批准号: 10591417
• 负责人: Kevin J Clerkin
• 金额: $ 17.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591417
• 关键词: Adult; Affect; American; Angiography; Antibodies; Arteries; B-Lymphocytes; Biopsy; Blood Cells; Blood Vessels; Blood flow; Blood specimen; Cardiac; Cardiac Catheterization Procedures; Cardiology; Catheterization; Cause of Death; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials Design; Clone Cells; Coronary; Coronary Angiography; Coronary Arteriosclerosis; Coronary artery; Cytokine Gene; Data; Detection; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic Procedure; Diffuse; Disease; Dobutamine Stress Echocardiography; Epicardium; Event; Exhibits; Fibrosis; Functional disorder; Future; Gene Mutation; Genes; Gifts; Goals; Guidelines; Heart Transplantation; Heart failure; Hematology; Hematopoiesis; Human; Image; Immune; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Ischemia; K-Series Research Career Programs; Life; Macrophage; Measurement; Measures; Mediating; Mentors; Mentorship; Modality; Organ; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Perfusion; Persons; Phenotype; Physicians; Physiology; Plasma Cells; Population; Positioning Attribute; Positron-Emission Tomography; Proliferating; Recommendation; Research; Research Personnel; Research Training; Risk; Risk Factors; Smooth Muscle; Stress Tests; Testing; Thick; Training; Translational Research; Transplant Recipients; Transplantation; Transplantation Immunology; United States; Vascular Diseases; Work; atherosclerosis risk; biobank; blood flow measurement; career; career development; chemokine; cytokine; experience; follow-up; heart allograft; heart imaging; improved; individual patient; meetings; mortality; mouse model; multidisciplinary; multimodality; novel; novel diagnostics; peripheral blood; post-transplant; pressure; prognostic; research data dissemination; research study; retransplantation; routine screening; screening; standard care; targeted treatment; translational study

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.

项目摘要/摘要 拟议的K23职业发展奖将使Kevin Clerkin博士建立独立 研究职业在心脏同种异体血管病（CAV）的诊断和机制方面具有专业知识。博士 克莱尔金（Clerkin）是临床晚期心力衰竭和移植心脏病专家，其长期目标是优化结果 相对于CAV的心脏移植受者。但是，需要进一步的培训才能实现这一目标。作为 这样，他已经组建了一个具有个人专业知识的多学科导师团队：（1）移植心脏病学 （2）移植免疫学（3）临床试验设计和行为（4）多模式心脏成像和（5）研究 传播。职业发展计划包括正式课程和移植中的指导会议 免疫学和临床试验设计。此外，它涉及活动和职业的指导经验 发展，研究传播和授予技巧。心脏移植是黄金标准治疗 对于最终的心力衰竭，每年遭受约25万美国人的折磨。鉴于骑士是死亡的原因 对于1/3的移植患者，有必要提高我们的理解和诊断CAV的能力。这 这项K23研究培训的主要目标是改善CAV的诊断和确定机制 煽动早期CAV，以为未来的研究奠定基础，以测试针对该途径的疗法。 该提案包括两项相互关联的研究，以通过临床和翻译来实现这一目标 研究。首先，我们假设基于生理的筛查（测量冠状动脉流动或 冠状动脉储备[CFR]）将改善CAV对传统血管造影的诊断。我们也是 假设在非侵入性心脏PET扫描上测量的CFR将与使用A的CFR相关 冠状动脉血管造影期间的压力线，从而允许进行新的主要非侵入性筛查 方法。在第二次翻译研究中，我们将利用研究1的仔细的CAV表型来探索 不确定电势的克隆造血（CHIP）作为早期CAV的潜在机制。成人筹码 与炎症性巨噬细胞增加有关，与动脉粥样硬化的风险增加有关 趋化因子和细胞因子。基于我们以前的工作，目前尚无其对CAV的影响 鉴定围绕重新载体的患者冠状动脉动脉的巨噬细胞种群，我们 假设芯片患者的CAV风险会增加。靶向基因测序将是 在我们生物库中的患者的外周血样本上进行，以检测芯片的存在 并评估其与早期CAV的关联。这项K23提议将定位克莱尔金博士，以实现他的目标 1）改善CAV的诊断，2）确定在优化CAV相关的患者结果的新目标 - 心脏移植和3）促进他的发展成为移植领域的独立研究者 心脏病学。