Supply and Demand: Oxygen and Workload Regulate Cardiomyocyte Proliferation

供需：氧气和工作量调节心肌细胞增殖

基本信息

批准号：
10572541
负责人：
Hesham Sadek
金额：
$ 107.18万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2030-01-31
项目状态：
未结题

项目摘要

Heart failure is a devastating disease with mortality rates exceeding many malignancies. The pathophysiological basis of systolic heart failure lies in the inability of the adult mammalian heart to regenerate lost or damaged myocardium. Although limited cardiomyocyte turnover does in fact occur in the adult mammalian heart, it is insufficient for restoration of contractile function following injury. In contrast to the adult mammalian heart, my group has shown that newborn mammals have a remarkable endogenous myocardial regenerative capacity, mediated by proliferation of preexisting cardiomyocytes. Nevertheless, the mere realization that the heart is not a post-mitotic organ created a lot of excitement in the past two decades and led to a flurry of bench and clinical studies aimed at outlining the cardiac regenerative potential of various cell types. While many of these studies may hold therapeutic promise, mounting evidence suggest that cell therapy may enhance some endogenous repair or regenerative mechanisms such as stimulation of cardiomyocyte proliferation. Importantly, current evidence suggests that both the regenerative ability of the early postnatal heart, and cardiomyocyte turnover in the adult heart are mediated by proliferative competency of pre-existing cardiomyocytes. However, mechanisms of regulation of mammalian cardiomyocyte cell cycle arrest shortly after birth remain poorly understood. Therefore, we believe that a program focused on understanding mechanisms of cardiomyocyte cell cycle regulation could inform future therapeutic interventions for heart regeneration. Our studies are focused on three broad questions: 1) Is loss of the regenerative capacity of the mammalian myocardium an evolutionary tradeoff to gain metabolic efficiency? 2) How is the slow turnover of cardiomyocytes in the adult heart regulated? 3) Does cardiac mechanical load represent a regenerative block

心力衰竭是一种毁灭性的疾病，其死亡率超过许多恶性肿瘤。收缩性心力衰竭的病理生理学基础在于成人的无力哺乳动物心脏再生丢失或受损的心肌。虽然有限心肌细胞更新确实发生在成年哺乳动物的心脏中，但还不够用于恢复受伤后的收缩功能。与成年哺乳动物相比我的团队已经证明，新生哺乳动物具有显着的内源性心肌再生能力，由先前存在的增殖介导心肌细胞。然而，仅仅认识到心脏不是有丝分裂后的管风琴在过去的二十年里引起了极大的轰动，并引发了一系列的板凳和风琴风潮。旨在概述各种细胞类型的心脏再生潜力的临床研究。虽然其中许多研究可能具有治疗前景，但越来越多的证据表明细胞疗法可能会增强一些内源性修复或再生机制，例如作为心肌细胞增殖的刺激。重要的是，目前的证据表明出生后早期心脏的再生能力和心肌细胞的周转率成人心脏是由预先存在的心肌细胞的增殖能力介导的。然而，哺乳动物心肌细胞细胞周期的调控机制很快就停滞了出生后仍然知之甚少。因此，我们认为一项计划的重点是了解心肌细胞细胞周期调节机制可以为未来提供信息心脏再生的治疗干预。我们的研究主要集中在三个广泛的领域问题：1）哺乳动物心肌再生能力的丧失是否与进化权衡以获得代谢效率？ 2）周转慢怎么办？成人心脏中的心肌细胞受到调节吗？ 3）心脏机械负荷代表再生块