Role of cGAS-STING in cardiomyocyte cell cycle regulation

cGAS-STING 在心肌细胞周期调节中的作用

• 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
• 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

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， 心肌对损伤的反应，由于成年心脏无法替代丢失或受损的心脏而加重 心肌细胞我们的实验室之前已经概述了新生儿的再生能力 哺乳动物的心脏，并概述了几种机制，调节这一过程。我们特别 证明新生儿心脏的内源性再生能力是由以下因素介导的 在心肌细胞退出细胞周期时， 出生后几天。我们描述了几种调节细胞周期退出的基本机制 心肌细胞，包括自发的DNA损伤，这是由于增加 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），其介导心肌细胞的细胞周期停滞，由此抑制剂 DDR延长心肌细胞增殖窗口。我们还研究了其他潜在的 DNA损伤的后果，即形成游离细胞质的微核 通常由有丝分裂过程中的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cGAS-STING在出生后心脏中在相同的时间范围内被诱导。 有趣的是，抑制cGAS导致心肌细胞的出生后窗口延长， 增殖因此，本项目将重点关注心肌细胞内cGAS-STING在心肌细胞凋亡中的作用。 调节心脏再生。我们将研究cGAS-STING在细胞中的激活机制。 心肌细胞，抑制cGAS-STING对心肌细胞增殖的影响，以及抑制cGAS-STING对心肌细胞增殖的影响。 调节心肌细胞中cGAS功能的下游机制。