ISCHEMIC MITRAL REGURGITATION: FROM MECHANISM TO THERAPY

描述(申请人提供)：项目摘要。候选人是一名心脏病专家，他在一个促进临床和基础科学家之间强烈互动的环境中，使用先进的非侵入性成像技术研究关于瓣膜心脏病的生理学假说。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)开发针对缺血性MR的新疗法，解决其基本机制；2)通过新的方向和合作扩大科学努力的范围；以及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。新方向包括在细胞和分子水平上了解缺血性MR对左室重构的影响以及这种重构的可逆性(与Roger Hajjar博士合作)；应用细胞和聚合物方法进行心室重建以逆转缺血性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，并应用从工作台到床边的知识来确定早期的、有可能治疗的形式(与Susan Slagenhaupt博士一起)；以及将概念从二尖瓣扩展到三尖瓣返流(与Carlos Duran博士一起)。这位候选人有良好的导师记录，支持向独立的职业生涯过渡，这一点得到了理查德·波普卓越教学奖的认可。更新的K24支持对于建立和资助心脏成像、左室重塑和分子遗传学的跨学科项目至关重要。该研究项目验证了中心假设，即缺血性MR可以通过重新排列叶与其心室附件来治疗。K24的更新将支持一个新的临床方向，与运动生理学领域的领先者合作，测试运动充分认识的缺血性MR可以强烈预测冠状动脉介入治疗后功能受限、左室重构和不良预后的假设。相关性：缺血性MR是冠状动脉疾病的常见并发症，可使晚期死亡率翻倍。现有的修复令人失望；需要针对左心室根本性变化的新疗法来减少相关的重塑和心力衰竭。MVP中的MR也可以导致持久的左室损伤，发现其负责任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调查人员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.