REGULATION OF CARDIOMYOCYTE GROWTH

正常发育期间心脏质量的增加以分化的心肌细胞的增殖为特征。 心肌细胞。出生后，心肌细胞周期活动率急剧下降， 随后心肌质量的增加很大程度上是由于心肌细胞肥大。 这些发育过程中的异常可能会导致先天性心脏缺陷。此外， 出生后缺乏实质性的心肌细胞周期活动，加上心肌细胞丢失(通过 细胞凋亡和/或其他机制)，对新生儿患者的发病率和死亡率有重要影响 充血性心力衰竭。我们已经生成了一些小鼠模型，它们展示了增强的 胚胎和出生后的心肌细胞周期活动。我们还生成了鼠标 在新生儿时期表现出肥大生长减少并且对损伤有抵抗力的模型- 靶向表达BmpIO诱导心肌细胞凋亡。建议数 实验将利用这些模型来探索心肌细胞凋亡和增殖的调节 新生儿心力衰竭时心肌细胞的生长。具体目标1a将检验假设 BmpIO的表达可以对儿童模型的获得性损伤起到心脏保护作用 人类的心力衰竭(即蒽环类药物的心脏毒性和病毒性心肌炎)。特定目标1b将测试 假设BmpIO在出生后心脏中通过旁分泌途径发挥作用，并将决定 心肌细胞对细胞因子介导的心肌保护的反应时间。特定目标 2A将检验抑制肥大生长使出生后心肌细胞更多的假设 易受细胞周期重入的影响。特定目标2b将检验心肌细胞诱导的假设 自行车运动可以逆转先天性和获得性损伤的不良后果，这些损伤导致 儿童期心力衰竭。拟议的研究将从计划赠款的组织中受益匪浅 应用，因为在其他项目中开发的许多试剂、技术和鼠标模型将 在这里用过。这个项目的最终目标是了解心肌细胞如何调节 可以利用细胞凋亡和增生的心肌细胞生长来保护高危心肌，和/或 促进新的心脏组织的形成，在儿童心力衰竭的背景下。

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.