Project 3 - Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte Proliferation

项目3 - 脯氨酸代谢在哺乳动物心肌细胞增殖调节中的作用

基本信息

批准号：
10677735
负责人：
Hesham Sadek
金额：
$ 43万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677735
关键词：
Adult Biological Process Birth Cardiac Myocytes Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cessation of life Chronic Citric Acid Cycle Competence Complex Cytoplasm DNA Damage Data Enzymes Exposure to Failure Family suidae Genetic Heart Heart failure Hypoxia Hypoxia Inducible Factor Injury Malate-Aspartate Shuttle Pathway Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Muscle Muscle Cells Myocardial NADP Natural regeneration Neonatal Newborn Infant Oxidation-Reduction Oxidative Phosphorylation Oxygen Physiological Population Process Proliferating Proline Proline Dehydrogenase Proteomics Regenerative capacity Regulation Reporting Respiration Role Signal Transduction Source Testing Transcriptional Regulation Ventricular cardiac regeneration environmental change enzyme pathway gain of function inhibitor loss of function metabolomics mitochondrial metabolism mouse model myocardial hypoxia porcine model postnatal regenerative response response to injury transcriptomics

项目摘要

ABSTRACT (Project 3) Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte Proliferation Heart failure progression is a complex biological process that is precipitated by the maladaptive myocardial response to injury, compounded by failure of the adult heart to replace lost or damaged cardiomyocytes. Our lab has previously outlined the regenerative capacity of the newborn mammalian heart and outlined several mechanisms that regulate this process. Specifically, we demonstrate that the endogenous regenerative capacity of the newborn heart is mediated by proliferation of preexisting cardiomyocytes and is lost when cardiomyocytes exit cell cycle within a few days after birth. We described several fundamental mechanisms that regulate cell cycle exit of cardiomyocytes, including spontaneous DNA damage that occurs as a result of increased mitochondrial oxidative phosphorylation. Subsequently, we demonstrated that gradual severe systemic hypoxia can induce cardiomyocyte proliferation in the adult mouse heart and is associated with decreased DNA damage. These finding suggest that oxygen metabolism is an upstream signal that mediates postnatal cardiomyocyte cell cycle in the postnatal heart. Intriguingly, we found that proline metabolism was markedly upregulated in regenerative cardiomyocytes under hypoxic conditions. From a mechanistic standpoint, we want to better understand the factors that regulate cardiomyocyte proliferation under hypoxia. Therefore, this proposal will examine the role of proline metabolism in regulation of cardiomyocyte adaptation and proliferation under hypoxia in both mice and pigs. In addition, we will examine the role of Hypoxia inducible factors (Hifs) in regulation of proline metabolism and cardiomyocyte proliferation in the neonatal heart and under hypoxic conditions.

抽象的（项目3）脯氨酸代谢在哺乳动物心肌细胞增殖调节中的作用心力衰竭进展是一个复杂的生物过程，由心肌适应不良引起对损伤的反应，加上成人心脏无法替代丢失或受损的心肌细胞。我们的实验室之前概述了新生哺乳动物心脏的再生能力，并概述了几种调节这一过程的机制。具体来说，我们证明内源再生能力新生心脏的功能是由先前存在的心肌细胞的增殖介导的，并且当心肌细胞出生后几天内退出细胞周期。我们描述了调节细胞的几种基本机制心肌细胞的周期退出，包括由于增加的DNA而发生的自发DNA损伤线粒体氧化磷酸化。随后，我们证明逐渐严重的全身缺氧可诱导成年小鼠心脏中的心肌细胞增殖，并与减少 DNA 损伤有关。这些发现表明氧代谢是介导出生后心肌细胞的上游信号产后心脏的循环。有趣的是，我们发现脯氨酸代谢在缺氧条件下心肌细胞的再生。从机制的角度来看，我们希望更好了解缺氧条件下调节心肌细胞增殖的因素。因此，本提案将检查脯氨酸代谢在缺氧条件下调节心肌细胞适应和增殖中的作用在小鼠和猪中。此外，我们将研究缺氧诱导因子 (Hifs) 在调节中的作用新生儿心脏和缺氧条件下脯氨酸代谢和心肌细胞增殖。