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

• 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
• 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

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.

摘要 （项目3） 脯氨酸代谢在哺乳动物心肌细胞增殖调控中的作用 心力衰竭进展是一个复杂的生物学过程， 对损伤的反应，由于成年心脏无法取代丢失或受损的心肌细胞而加剧。我们实验室 先前已经概述了新生哺乳动物心脏的再生能力，并概述了几个 调节这一过程的机制。具体来说，我们证明，内源性再生能力， 新生心脏的增殖是由预先存在的心肌细胞的增殖介导的， 在出生后几天内退出细胞周期。我们描述了几种调节细胞生长的基本机制， 心肌细胞的周期退出，包括由于心肌细胞增殖增加而发生的自发DNA损伤。 线粒体氧化磷酸化。随后，我们证明了逐渐严重的全身缺氧， 可以诱导成年小鼠心脏中的心肌细胞增殖，并与降低的DNA损伤有关。 这些结果表明，氧代谢是一个上游信号，介导出生后心肌细胞 出生后心脏的周期。有趣的是，我们发现，脯氨酸代谢显着上调 缺氧条件下的再生心肌细胞。从机械的角度来看，我们希望更好地 了解缺氧条件下调节心肌细胞增殖的因素。因此，这项建议将 研究脯氨酸代谢在调节心肌细胞缺氧适应和增殖中的作用 在老鼠和猪身上。此外，我们还将研究缺氧诱导因子（Hifs）在调节细胞凋亡中的作用。 脯氨酸代谢和心肌细胞增殖在新生儿心脏和缺氧条件下。