ISCHEMIC MITRAL REGURGITATION: FROM MECHANISM TO THERAPY

描述（由申请人提供）：项目概述。该候选人是一名心脏病专家，在促进临床和基础科学家之间密切互动的环境中，使用先进的无创成像技术研究有关瓣膜性心脏病的生理假说。他的近期目标是开发更有效的治疗缺血性二尖瓣反流（MR）的方法。最初的K24奖使以下目标取得了广泛的进展：1)开发缺血性MR的新疗法，解决其基本机制；2)通过新的研究方向和合作扩大科学努力的范围；3)通过这些新的研究方向和共同指导扩大培训和指导的机会。新的方向包括了解缺血MR对左室重塑的影响以及细胞和分子水平上这种重塑的可逆性（与Roger Hajjar博士合作）；应用细胞和聚合物方法进行心室恢复以逆转缺血性MR（与Philippe Menasche教授合作）；确定二尖瓣脱垂（MVP）的遗传基础，这是MR的另一个原因，并将从实验室到床边的知识应用于早期识别，潜在的可治疗形式（与Susan Slaugenhaupt博士一起）；并将概念从二尖瓣反流扩展到三尖瓣反流（与卡洛斯·杜兰博士一起）。候选人在支持向独立职业过渡方面有良好的指导记录，并获得了Richard Popp卓越教学奖的认可。重新支持K24是建立和资助心脏成像、左室重塑和分子遗传学跨学科项目的关键。该研究项目测试了缺血性MR可以通过重新调整小叶及其心室附件来治疗的中心假设。K24的更新将支持一个新的临床方向，与运动生理学的领导者合作，验证缺血性MR，充分了解运动，强有力地预测冠状动脉介入治疗后的功能限制，左室重塑和不良预后的假设。相关性：缺血性MR是冠状动脉疾病的常见并发症，使晚期死亡率增加一倍。现有的维修工作令人失望；需要针对左室根本改变的新疗法来减少相关的重构和心力衰竭。MVP中的MR也可引起持久的左室损伤，发现其相关的遗传缺陷具有治疗前景。这两个领域都为指导下一代成功的研究者提供了越来越多的机会。

DESCRIPTION (provided by applicant): Project Summary. The candidate is a cardiologist who studies physiologic hypotheses regarding valvular heart disease using advanced noninvasive imaging techniques in an environment that fosters strong interactions between clinical and basic scientists. His immediate goal is to develop more effective therapies for ischemic mitral regurgitation (MR). The initial K24 Award has enabled extensive progress toward the following goals: 1) developing novel therapies for ischemic MR that address its fundamental mechanism; 2) expanding the scope of the scientific endeavor through new directions and collaborations: and 3) expanding opportunities for training and mentoring through these new research directions and co-mentorships. New directions include understanding the impact of ischemic MR on LV remodeling and the reversibility of such remodeling at a cellular and molecular level (with Dr. Roger Hajjar); applying cell and polymer approaches to ventricular restoration for reversing ischemic MR (with Prof. Philippe Menasche); determining the genetic basis of mitral valve prolapse (MVP), another cause of MR, and applying knowledge from bench to bedside to identify early, potentially treatable forms (with Dr. Susan Slaugenhaupt); and extending concepts from mitral to tricuspid regurgitation (with Dr. Carlos Duran). The candidate has a strong record of mentoring that supports transition to independent careers, as recognized by the Richard Popp Excellence in Teaching Award. Renewed K24 support is critical to build upon and fund interdisciplinary programs in cardiac imaging, LV remodeling and molecular genetics. The research program tests the central hypothesis that ischemic MR can be treated by realigning the leaflets with their ventricular attachments. The K24 renewal will support a new clinical direction, in collaboration with leaders in exercise physiology, to test the hypothesis that ischemic MR, fully appreciated with exercise, strongly predicts functional limitation, LV remodeling, and adverse prognosis following coronary interventions. Relevance: Ischemic MR is a common complication of coronary disease, doubling late mortality. Existing repairs are disappointing; new therapies that target fundamental changes in the LV are needed to reduce the associated remodeling and heart failure. MR in MVP can also cause lasting LV impairment, and discovering its responsible genetic defects has therapeutic promise. Both areas provide growing opportunities to mentor the next generation of successful investigators.