权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of Cardiomyocyte Turnover in the Adult Mammalian Heart

成年哺乳动物心脏心肌细胞周转的调节

基本信息

批准号：
9463489
负责人：
Hesham Sadek
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9463489
关键词：
Acute Adult Age-Years Aging Biology Birth Cardiac Cardiac Myocytes Cardiovascular system Cell Cycle Cell Cycle Arrest Cell Size Characteristics Chest Chimeric Proteins Competence DNA Damage Data Exposure to Genetic Goals Heart Heart failure Homeostasis Human Hypoxia Injury Ionizing radiation Lasers Longevity Maintenance Maps Measurable Mediating Mediator of activation protein Messenger RNA Microdissection Mitochondria Modeling Muscle Cells Names Nature Neonatal Oxygen Pathology Population Procollagen-Proline Dioxygenase Proteins Radiation Induced DNA Damage Reactive Oxygen Species Regulation Role Secondary to Signal Transduction Tamoxifen Therapeutic Time Transforming Growth Factor beta Transgenic Mice Up-Regulation biological adaptation to stress cardiac regeneration insight mouse model oxidative DNA damage postnatal promoter public health relevance regenerative response tool transcriptome sequencing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Regulation of mammalian cardiomyocyte cell cycle has been a central question in cardiovascular biology for decades, secondary to the burden of heart failure. Although the adult heart does not have a significant regenerative potential, it has recently become clear that measurable cardiomyocyte turnover does in fact occur in the adult heart, mediated by proliferation of pre-existing cardiomyocytes. In fact, the rate of cardiomyocyte turnover in the adult human heart is about 2% per year between 20 and 40 years of age, and 0.5 -1% per year thereafter. While this rate of myocyte turnover is insufficient for heart regeneration following injury, it is critical for constant replacement of dead or damaged myocytes. As a result, close to 45% of cardiomyocytes in a human heart are replaced throughout its lifespan. We recently showed that an important mechanism of cell cycle arrest of the majority of cardiomyocytes postnatally is mitochondrial reactive oxygen species (ROS)-mediated oxidative DNA damage, and activation of DNA damage response (DDR). Moreover, we developed the first mouse model to fate map the rare population of cycling cardiomyocytes in the postnatal heart, and we found that these cycling cardiomyocytes are characterized by upregulation of hypoxic stress response and are protected from the oxidative DNA damage. Therefore, we propose to examine the mechanism of cardiomyocyte turnover in the adult mammalian heart using the fate-mapping model that we developed. We will first characterize the dynamics of hypoxic cardiomyocyte turnover in the neonatal, adult and ageing heart. We will also examine the role of DNA damage in regulation of hypoxic cardiomyocyte turnover. Finally, we will investigate the endogenous mechanism of maintenance of hypoxia signaling in cycling cardiomyocytes. Achieving the goals of this proposal will provide new insights into the mechanism of cardiomyocyte turnover in the adult mammalian heart. We hope to exploit these results to develop new strategies to enhance cardiomyocyte renewal in the failing heart.