Angiogenesis and Cardiac Growth as Heart Failure Therapy

描述(由申请人提供)： 心血管疾病是世界范围内死亡的主要原因。在美国，每年有100万人死于心血管疾病，500万人患有充血性心力衰竭，另有500万人患有严重的无症状左心功能障碍，很快就会发展为心力衰竭，预计随着人口老龄化，这一数字将大幅上升。目前治疗心力衰竭的方法包括对前负荷和后负荷的药理学优化，以及非常有限的重建或替代选择。该研究项目的总体目标是通过诱导血管生成和局部心肌生长这两种相互关联的分子策略来增强天然心肌细胞的功能。在缺血性心肌病的啮齿动物模型中，重组腺病毒将被用来提供血管生成因子肝细胞生长因子和营养因子生长激素的高水平、定位的基因表达。随后将使用腔内压、容量电导微导管和升主动脉心输出量监测仪在活体内评估对心肌功能的影响。对心脏重塑的影响也将被评估。有关逆转心肌缺血、抗细胞凋亡和过度收缩的具体作用机制将进行深入研究。最终目标将是开发一种综合心力衰竭疗法，促进天然心肌细胞生长，同时增加心肌血流量。 候选人寻求利用这一拟议的研究职业奖项提供的时间和机会从事集中的学术活动，致力于研究心力衰竭的基本分子和细胞机制，设计与临床护理相关的创新治疗策略，获得额外的结构化教学教育和培训，获得新的科学知识和研究技术，并发展成为一名有竞争力的独立研究人员的关键技能。候选人的机构、赞助商和主席提供了一个独特的支持性、高素质、教育刺激的环境，非常有助于实现这些目标。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of mortality worldwide. In the U.S., one million people die annually of cardiovascular disease, five million people live with congestive heart failure, and another five million have significant asymptomatic left ventricular dysfunction soon to progress to heart failure, numbers that are predicted to rise dramatically with the progressively aging population. Current therapies for heart failure consist of pharmacologic optimization of preload and afterload together with very limited reconstructive or replacement options. The overall objective of the proposed research project is to augment native cardiomyocyte function through two interrelated molecular strategies of inducing angiogenesis and localized myocardial growth. In a rodent model of ischemic cardiomyopathy, recombinant adenoviruses will be used to provide high-level, localized gene expression of the angiogenic agent hepatocyte growth factor and the trophic agent growth hormone. Effects on myocardial function will then be assessed in vivo with an intracavitary pressure volume conductance microcatheter and an ascending aortic cardiac output monitor. Effects on ventricular remodeling will also be evaluated. Specific mechanisms of action pertaining to reversal of myocardial ischemia, anti-apoptosis, and hypercontractility will be studied in-depth. The ultimate goal will be to develop an integrated heart failure therapy which promotes native cardiomyocyte growth coupled with enhanced myocardial blood flow. The candidate seeks to utilize the time and opportunities provided by this proposed research career award to engage in a concentrated period of scholarly activity dedicated to studying basic molecular and cellular mechanisms in heart failure, to design innovative treatment strategies pertinent to clinical care, to obtain additional structured didactic education and training, to acquire new scientific knowledge and research techniques, and to develop critical skills towards becoming a competitive, independent investigator. The candidate's institution, sponsor, and chairman provide a uniquely supportive, high-caliber, educationally stimulating environment highly conducive to the achievement of these goals.