REGULATION OF CARDIOMYOCYTE GROWTH

在正常发育过程中，心脏质量增加的特征是分化的 心肌细胞出生后，心肌细胞的细胞周期活动率急剧下降， 随后心脏质量的增加主要是心肌细胞肥大的结果。 这些发育过程的异常可能导致先天性心脏缺陷。而且 缺乏实质性的出生后心肌细胞细胞周期活动，加上心肌细胞损失（通过 细胞凋亡和/或其他机制），显著地导致新生儿患者的发病率和死亡率 充血性心力衰竭我们已经产生了许多小鼠模型，其表现出增强的 胚胎期和出生后的心肌细胞周期活动。我们还生成了鼠标 在新生儿生命期间表现出减少的肥大性生长并且对损伤具有抗性的模型， 诱导心肌细胞凋亡作为靶向BmpIO表达的结果。拟议 实验将使用这些模型来探索心肌细胞凋亡和增生的调节。 新生儿心力衰竭时心肌细胞的生长。具体目标1a将检验以下假设： BmpIO表达可以对模拟儿童的获得性损伤发挥心脏保护活性 人类心力衰竭（即蒽环类药物心脏毒性和病毒性心肌炎）。具体目标1b将测试 假设BmpIO功能通过旁分泌途径在出生后的心脏，也将确定 心室心肌细胞对苦参碱介导的心脏保护作用保持响应的时间。具体目标 图2a将检验抑制肥大生长使出生后心肌细胞 容易重新进入细胞周期。特异性目的2b将检验心肌细胞的诱导 自行车活动可以扭转先天性和后天性损伤的不良后果， 儿童心力衰竭。拟议的研究将大大受益于计划赠款的组织 应用，因为其他项目中开发的许多试剂、技术和小鼠模型将被 在这里使用。这个项目的最终目标是了解心肌细胞的调节是如何进行的。 细胞凋亡和增生性心肌细胞生长可用于保护危险心肌，和/或 促进新的心脏组织的形成，在儿童心力衰竭的情况下。

Increases in cardiac mass during normal development are characterized by proliferation of differentiated cardiomyocytes. After birth there is a dramatic reduction in the rate of cardiomyocyte cell cycle activity, and subsequent increases in cardiac mass occur largely as a consequence of cardiomyocyte hypertrophy. Abnormalities in these developmental processes can give rise to congenital heart defects. Moreover, the absence of substantive postnatal cardiomyocyte cell cycle activity, coupled with cardiomyocyte loss (via apoptosis and/or other mechanisms), contributes significantly to morbidity and mortality in neonatal patients with congestive heart failure. We have generated a number of mouse models which exhibit enhanced cardiomyocyte cell cycle activity during embryonic and postnatal life. We have also generated mouse models that exhibit reduced hypertrophic growth during neonatal life and which are resistant to injury- induced cardiomyocyte apoptosis as a consequence of targeted BmpIO expression. The proposed experiments will use these models to explore the regulation of cardiomyocyte apoptosis and hyperplastic cardiomyocyte growth in the setting of neonatal heart failure. Specific Aim 1a will test the hypothesis that BmpIO expression can exert cardioprotective activity in response to acquired injuries which model childhood heart failure in humans (namely anthracycline cardiotoxicity and viral myocarditis). Specific Aim 1b will test the hypothesis that BmpIO functions via paracrine pathways in the postnatal heart, and will also determine how long ventricular cardiomyocytes remain responsive to cytokine-mediated cardioprotection. Specific Aim 2a will test the hypothesis that inhibition of hypertrophic growth renders postnatal cardiomyocytes more susceptible to cell cycle re-entry. Specific Aim 2b will test the hypothesis that induction of cardiomyocyte cell cycle activity can reverse the adverse consequences of congenital and acquired injuries which give rise to childhood heart failure. The proposed studies will benefit greatly from the organization of the Program Grant application, in that many reagents, techniques and mouse models developed in the other projects will be used here. The ultimate goal of this project is to gain an understanding of how regulation of cardiomyocyte apoptosis and hyperplastic cardiomyocyte growth can be exploited to protect at-risk myocardium, and/or to promote the formation of new heart tissue, in the setting of childhood heart failure.