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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10572541
• 关键词: Address; Adult; Birth; Cardiac; Cardiac Myocytes; Cell Cycle Arrest; Cell Cycle Regulation; Cell Therapy; Clinical Research; Competence; Disease; Future; Heart; Heart failure; Injury; Malignant Neoplasms; Mammals; Mediating; Metabolic; Myocardial; Myocardium; Natural regeneration; Neonatal; Newborn Infant; Organ; Oxygen; Proliferating; Regenerative capacity; Regulation; Systolic heart failure; Therapeutic; Therapeutic Intervention; Vertebrates; Workload; cardiac regeneration; cell type; mechanical load; mortality; postmitotic; postnatal; programs; regeneration potential; regenerative; repaired; restoration

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基础在于成年人不能 哺乳动物心脏再生丢失或受损的心肌。虽然有限 事实上，成年哺乳动物的心脏中确实存在心肌细胞更新，但这是不充分的。 用于恢复损伤后的收缩功能。与成年哺乳动物相比， 心脏，我的团队已经表明，新生哺乳动物有一个显着的内源性 心肌再生能力，由预先存在的 心肌细胞然而，仅仅意识到心脏不是有丝分裂后的 管风琴在过去的二十年里创造了很多兴奋，并导致了一系列的板凳和 旨在概述各种细胞类型的心脏再生潜力的临床研究。 虽然这些研究中有许多可能具有治疗前景，但越来越多的证据表明， 细胞疗法可以增强一些内源性修复或再生机制， 刺激心肌细胞增殖。重要的是，目前的证据表明， 出生后早期心脏的再生能力， 成人心脏由预先存在的心肌细胞的增殖能力介导。 然而，哺乳动物心肌细胞周期的调控机制， 出生后，人们对它知之甚少。因此，我们认为， 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。我们的研究集中在三个广泛的 问题：1）哺乳动物心肌再生能力的丧失是否是 进化权衡以获得代谢效率？2)如何缓慢周转 成人心脏中的心肌细胞受到调节？3)心脏机械负荷是否代表 再生块