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：
9240660
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/9240660
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.

描述（由申请人提供）：几十年来，哺乳动物心肌细胞周期的调节一直是心血管生物学的一个核心问题，继发于心力衰竭的负担。尽管成人心脏不具有显着的再生潜力，但最近已经清楚这一点。事实上，可测量的心肌细胞更新确实发生在成人心脏中，这是由预先存在的心肌细胞的增殖介导的。事实上，成年人心脏中心肌细胞更新的速率在20岁至20岁之间每年约为2%。 40 岁，此后每年 0.5 -1% 虽然这种心肌细胞更新率不足以支持受伤后的心脏再生，但它对于不断更换死亡或受损的心肌细胞至关重要。我们最近发现，大多数心肌细胞出生后细胞周期停滞的一个重要机制是线粒体活性氧 (ROS) 介导的氧化性 DNA 损伤和 DNA 损伤的激活。此外，我们开发了第一个小鼠模型来绘制出生后心脏中罕见的心脏循环心肌细胞群的命运图谱，我们发现这些循环心肌细胞的特点是缺氧应激反应上调，并且免受氧化DNA损伤。因此，我们建议使用我们开发的命运图谱模型来研究成年哺乳动物心脏中心肌细胞更新的机制。我们将首先描述新生儿、成人和衰老过程中缺氧心肌细胞更新的动态。我们还将研究 DNA 损伤在缺氧心肌细胞周转调节中的作用，最后，我们将研究循环心肌细胞中缺氧信号传导的内源性机制。我们希望利用这些结果来开发新的策略来增强衰竭心脏中的心肌细胞更新。