Molecular Determinants of Cardiomyocyte Proliferation

心肌细胞增殖的分子决定因素

基本信息

批准号：
7442186
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
项目类别：
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/7442186
关键词：
Active Learning Address Adult Advisory Committees Aging Award Biology of Aging Burn injury Cardiac Cardiac Myocytes Cardiology Cardiovascular system Cause of Death Cell Proliferation Cells Cessation of life Chromatin Commit Complex Congestive Heart Failure Data Development Doctor of Philosophy Dominant-Negative Mutation Drug Delivery Systems Elderly Embryo Embryonic Development Gene Targeting General Hospitals Genes Goals Heart Heart Diseases Heart failure Hospital Departments Hyperplasia Hypertension Immunoprecipitation Journals Learning Libraries Life Massachusetts Mediating Mentors Modification Molecular Mutation Myocardial Myocardial Infarction Natural regeneration Numbers Pathway interactions Pattern Phenotype Physiology Play Population Prevention Protein Overexpression Proteins Reagent Records Regulation Research Research Institute Research Personnel Research Proposals Resources Role System Testing Therapeutic Tissue-Specific Gene Expression Tissues Transcriptional Regulation Transgenic Organisms United States Workload Yeasts Zebrafish aging population beta catenin c-myc Genes cardiogenesis design experience helicase inhibitor/antagonist mortality mutant novel novel therapeutics outcome forecast prevent programs research study transcription factor yeast two hybrid system

项目摘要

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（申请人提供）：研究提案：心脏病是 65 岁以上人群的第一大死因，84% 的心脏病死亡发生在老年人群中。如果存在刺激心肌细胞增殖和心脏再生的治疗策略，许多这样的死亡是可以避免的。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障碍。最近的数据表明，解旋酶蛋白 Reptin 在调节心肌细胞增殖中发挥着重要作用，因为斑马鱼 Reptin（称为 liebeskummer）的激活突变会导致胚胎心肌增生。该提案的具体目的是阐明 Reptin 调节心肌细胞增殖的机制。独特的实验方法依赖于候选者和liebeskummer突变体开发的几种试剂。具体目标 I 通过开发和分析转基因斑马鱼来解决 Reptin 是否是心肌细胞增殖所必需的，该斑马鱼在胚胎心肌细胞中过度表达 Reptin 的显性失活抑制剂。 Specific Aim II 测试斑马鱼心脏中 Reptin 与转录因子 β-catenin 和 c-Myc 之间是否发生相互作用，如果是，则该相互作用是否是 Reptin 在心肌细胞增殖中的调节作用所必需的。 Specific Aim III 中的实验将通过分析野生型心脏和 Libeskummer 心脏之间的差异基因表达来确定 Reptin 的下游靶标。这些拟议的实验将有助于阐明 Reptin 在心肌细胞增殖调节中的作用，并确定刺激老年人群心肌细胞增殖和心脏再生的新药物靶点。候选人：C. Geoffrey Burns 博士，是马萨诸塞州总医院 (MGH) 心血管研究中心的研究员，该中心是一家致力于了解心血管发育、生理学和衰老的杰出研究机构。在奖励期间，麻省总医院心脏病科向伯恩斯医生投入了大量资源。伯恩斯博士将接受伯恩斯博士的主要指导。 Calum MacRae 和 Anthony Rosenzweig 共同拥有 25 年心血管研究经验，并拥有作为成功导师的记录。伯恩斯博士还组建了一个科学咨询委员会，其中包括两位心血管衰老专家（肯·米纳克博士和罗杰·哈贾尔博士）和一位卓有成就的斑马鱼发育遗传学家（莱恩·德拉蒙德博士）。伯恩斯博士将通过相关的实验室会议、期刊俱乐部、研讨会、科学会议和衰老生物学的教学学习来补充体验式学习。最终，该奖项将帮助伯恩斯博士实现成为心脏再生领域的独立研究者和心血管衰老专家的长期目标。