Molecular Determinants of Cardiomyocyte Proliferation

心肌细胞增殖的分子决定因素

• 批准号: 6758432
• 负责人: C. Geoffrey Burns
• 金额: $ 12.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758432
• 关键词: aging; cadherins; cardiac myocytes; cardiogenesis; cell growth regulation; cell proliferation; congestive heart failure; developmental genetics; dietary proteins; gene mutation; genetically modified animals; helicase; immunoprecipitation; nonmammalian vertebrate embryology; nuclear proteins; protein protein interaction; site directed mutagenesis; transcription factor; yeast two hybrid system; zebrafish

DESCRIPTION (provided by applicant): Research Proposal: Heart disease is the number one cause of death in people over age 65 and 84% of deaths caused by heart disease occur in the elderly population. Many of these deaths could be prevented if therapeutic strategies existed for stimulating cardiomyocyte proliferation and cardiac regeneration. As a prerequisite, the molecular pathways that regulate embryonic cardiomyocyte proliferation and the molecular barriers to proliferation in aging cardiomyocytes must be elucidated. Recent data suggest that a helicase protein, Reptin, plays a fundamental role in regulating cardiomyocyte proliferation since an activating mutation in zebrafish Reptin (called liebeskummer) causes embryonic myocardial hyperplasia. The specific aims of this proposal are designed to elucidate the mechanism by which Reptin regulates cardiomyocyte proliferation. The unique experimental approach relies on several reagents developed by the candidate and the liebeskummer mutant. Specific Aim I addresses whether Reptin is necessary for cardiomyocyte proliferation by developing and analyzing transgenic zebrafish that overexpress a dominant negative inhibitor of Reptin specifically in embryonic cardiomyocytes. Specific Aim II tests whether interactions between Reptin and the transcription factors beta-catenin and c-Myc occur in zebrafish heart and if so, whether the interactions are necessary for Reptin's regulatory role in cardiomyocyte proliferation. Experiments in Specific Aim III will identify downstream targets of Reptin by analyzing differential gene expression between wild-type and liebeskummer hearts. Together the proposed experiments will help elucidate Reptin's role in the regulator of cardiomyocyte proliferation and identify novel drug targets for stimulating cardiomyocyte proliferation and cardiac regeneration in the aging population. The candidate: The candidate, C. Geoffrey Burns Ph.D., is a fellow at Massachusetts General Hospital (MGH) in the Cardiovascular Research Center, a preeminent research institute devoted to understanding cardiovascular development, physiology, and aging. The MGH Department of Cardiology has committed numerous resources to Dr. Burns during the award period. Dr. Burns will receive primary guidance from Drs. Calum MacRae and Anthony Rosenzweig, who together have 25 years experience in cardiovascular research and track records as successful mentors. Dr. Burns has also assembled a Scientific Advisory Committee that includes two cardiovascular aging experts (Dr. Ken Minaker and Dr. Roger Hajjar) and an accomplished zebrafish developmental geneticist (Dr. lain Drummond). Dr. Burns will supplement experiential learning with relevant lab meetings, journal clubs, seminars, scientific meetings, and didactic learning the biology of aging. Ultimately, this award will aid Dr. Burns in achieving his long-term goals of becoming an independent investigator in the field of cardiac regeneration and expert in cardiovascular aging.

描述（由申请人提供）：研究建议：心脏病是65岁以上患者的死亡原因第一，死亡人数造成的死亡人数为老年人。如果存在刺激心肌细胞增殖和心脏再生的治疗策略，则可以预防这些死亡中的许多死亡。作为先决条件，必须阐明调节胚胎心肌细胞增殖的分子途径和衰老心肌细胞增殖的分子屏障。最近的数据表明，由于斑马鱼Reptin（称为Liebeskummer）激活突变会导致胚胎心肌增生，因此旋转酶蛋白Reptin在调节心肌细胞增殖中起着基本作用。该提案的具体目的旨在阐明reptin调节心肌细胞增殖的机制。独特的实验方法取决于候选人和Liebeskummer突变体开发的几种试剂。具体目的I通过开发和分析转基因斑马鱼是否过表达reptin的主要负面抑制剂，专门在胚胎心肌细胞中过度表达了主要的转基因斑马鱼。特定的AIM II测试Reptin与转录因子之间的相互作用是否发生在斑马鱼心中，如果是这样，是否需要相互作用对于Reptin在心肌细胞增殖中的调节作用是必需的。特定目标III中的实验将通过分析野生型和Liebeskummer心之间的差异基因表达来识别Reptin的下游靶标。提出的实验将共同阐明Reptin在心肌细胞增殖的调节剂中的作用，并确定新的药物靶标，以刺激衰老人群中刺激心肌细胞增殖和心脏再生。候选人：候选人C. Geoffrey Burns博士是心血管研究中心马萨诸塞州综合医院（MGH）的研究员，这是一家杰出的研究所，致力于了解心血管发展，生理学和衰老。 MGH心脏病学部在颁奖期间为伯恩斯博士提供了许多资源。伯恩斯博士将获得博士的主要指导。 Calum Macrae和Anthony Rosenzweig共同在心血管研究和记录方面拥有25年的经验，成为成功的导师。伯恩斯博士还组建了一个科学咨询委员会，其中包括两名心血管老龄化专家（Ken Minaker博士和Roger Hajjar博士）和一位成就卓著的斑马鱼发展遗传学家（Lain Drummond博士）。伯恩斯博士将通过相关的实验室会议，期刊俱乐部，研讨会，科学会议和教学学习衰老的生物学来补充体验式学习。最终，该奖项将有助于伯恩斯博士实现他成为心脏再生领域独立研究者和心血管衰老专家的长期目标。