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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：
10493840
负责人：
Hesham Sadek
金额：
$ 39.8万
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/10493840
关键词：
Adult Anaerobic Bacteria Biological Process Birth Cardiac Myocytes Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cessation of life Chronic Citric Acid Cycle Competence Complex 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 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 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.

摘要