Role of cGAS-STING in cardiomyocyte cell cycle regulation

cGAS-STING 在心肌细胞周期调节中的作用

基本信息

批准号：
10625952
负责人：
Hesham Sadek
金额：
$ 49.2万
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：
2023-04-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625952
关键词：
Adult Agonist Binding Biological Assay Biological Process Birth Calcineurin Cardiac Myocytes Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Chromosome Segregation Complex Consensus Cytoplasm Cytosol DNA DNA Binding DNA Damage DNA Repair Data Endoplasmic Reticulum Failure Genes Genetic Genetic Transcription Growth Heart Heart failure IRF3 gene Immune response Immune signaling Innate Immune Response Link Mediating Mitochondria Mitosis Modeling Molecular Myocardial Myocardium NF-kappa B Neonatal Newborn Infant Nuclear Oxidative Phosphorylation Oxidative Stress Pathway interactions Process Proliferating Property Proteins Publishing Regenerative capacity Regulation Role Stimulator of Interferon Genes System Testing Time cardiac regeneration cell type chemokine cytokine inhibitor loss of function micronucleus oxidative DNA damage postnatal prevent regenerative response response to injury

项目摘要

Project Summary 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. We also demonstrated that DNA damage activates DNA damage response (DDR), which mediates cell cycle arrest of cardiomyocytes whereby inhibitors of DDR prolong the window of cardiomyocyte proliferation. We also examined other potential consequences of DNA damage, namely the formation of micronuclei, which is free cytoplasmic DNA that often results from DNA damage during mitosis. Our preliminary results indicate that the micronuclei are detected in cardiomyocytes at the time of cell cycle arrest. We also found that the DNA sensing pathway cGAS-STING is induced in the postnatal heart within the same timeframe. Intriguingly, inhibiting cGAS results in prolongation of the postnatal window of cardiomyocyte proliferation. Therefore, this project will focus on the role of intra-cardiomyocyte cGAS-STING in regulation of heart regeneration. We will examine the mechanism of activation of cGAS-STING in cardiomyocytes, the effect of inhibiting cGAS-STING on cardiomyocyte proliferation, and the downstream mechanisms that regulate cGAS function in cardiomyocytes.

项目摘要心力衰竭进展是一个复杂的生物学过程，由不良适应性引起心肌对损伤的反应，成人心脏无法替换失去或损坏的情况加重心肌细胞。我们的实验室以前概述了新生儿的再生能力哺乳动物心脏并概述了调节此过程的几种机制。具体来说，我们证明新生儿的内源性再生能力是由先前存在的心肌细胞的扩散，当心肌细胞退出细胞周期时会丢失出生后几天。我们描述了调节细胞周期出口的几种基本机制心肌细胞的大量，包括由于增加而发生的自发DNA损伤线粒体氧化磷酸化。我们还证明了DNA损伤激活DNA 损伤反应（DDR），介导心肌细胞的细胞周期停滞，从而抑制剂 DDR延长心肌细胞增殖的窗户。我们还检查了其他潜力 DNA损伤的后果，即微核的形成，它是自由细胞质的在有丝分裂过程中DNA损伤引起的DNA。我们的初步结果表明在细胞周期停滞时，在心肌细胞中检测到微核。我们还发现 DNA传感途径在同一时间范围内诱导出产后心脏中诱导CGAS刺。有趣的是，抑制CGA会导致心肌细胞产后窗口的延长增殖。因此，该项目将重点介绍内形成型CGAS内的作用调节心脏再生。我们将检查CGAS刺激的机制心肌细胞，抑制CGAS刺对心肌细胞增殖的影响，以及调节CGA在心肌细胞中功能的下游机制。