Angiogenesis and Cardiac Growth as Heart Failure Therapy

血管生成和心脏生长作为心力衰竭的治疗

• 批准号: 6764935
• 负责人: Y Joseph Woo
• 金额: $ 13.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764935
• 关键词: angiogenesis; calcium transporting ATPase; cardiac myocytes; cardiovascular disorder therapy; disease /disorder model; gene delivery system; gene expression; gene therapy; heart circulation; heart failure; heart function; hepatocyte growth factor; immunocytochemistry; laboratory rat; muscle contraction; myocardial ischemia /hypoxia; nonhuman therapy evaluation; recombinant virus; somatotropin; transfection /expression vector

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.

描述（由申请人提供）： 心血管疾病是全球死亡的主要原因。 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，另外500万人具有显著的无症状左心室功能障碍，不久将发展为心力衰竭，预计随着人口的逐渐老龄化，这些数字将急剧上升。 目前心力衰竭的治疗包括前负荷和后负荷的药理学优化以及非常有限的重建或置换选择。 拟议的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，重组腺病毒将用于提供血管生成剂肝细胞生长因子和营养剂生长激素的高水平、局部基因表达。 然后将在体内使用腔内压力容积电导微导管和升主动脉心输出量监测仪评估对心肌功能的影响。 还将评价对心室重塑的影响。 将深入研究与逆转心肌缺血、抗细胞凋亡和过度收缩有关的具体作用机制。 最终的目标将是开发一种综合性心力衰竭治疗方法，促进天然心肌细胞生长，同时增强心肌血流。 候选人寻求利用这一拟议的研究职业奖提供的时间和机会，从事学术活动的集中时期，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，并发展关键技能，成为一个有竞争力的，独立的调查员。 候选人的机构，赞助商和主席提供了一个独特的支持，高素质，教育刺激的环境非常有利于实现这些目标。