Signaling mechanisms that mediate anoxia-induced cellular arrest

介导缺氧诱导的细胞停滞的信号机制

• 批准号: 9765339
• 负责人: Rachel Melissa Brewster
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765339
• 关键词: ATP phosphohydrolase; Acute; Adenosine Triphosphate; Adult; Anoxia; Binding; Brain; Cell Cycle; Cell Cycle Progression; Cells; Collaborations; Consumption; Cytosol; Data; Dependence; Development; Developmental Biology; Embryo; Endocytosis Inhibition; Energy-Generating Resources; Event; Exposure to; Family member; Genetic Transcription; Goals; Heart; Homeostasis; Hour; Human; Hypoxia; Injury; Kidney; Lead; Life; Mediating; Metabolic; Metabolism; NDRG1 gene; Na(+)-K(+)-Exchanging ATPase; Organ; Organ Transplantation; Organism; Oxidative Phosphorylation; Oxygen; Patients; Physiological; Post-Translational Regulation; Prevention; Process; Protein Family; Proteins; Proteomics; Pump; Regulation; Research; Research Personnel; Role; Signal Transduction; Signaling Molecule; Study models; Testing; Tissue Preservation; Translations; Work; Zebrafish; angiogenesis; blastocyst; cancer cell; cell cortex; cell type; deprivation; experience; in vitro testing; in vivo; ionic balance; metabolic rate; metabolomics; novel; novel therapeutics; prostate cancer cell; protective effect; protein distribution; response; therapeutic target; tissue/cell culture

PROPOSAL ABSTRACT Most organisms are highly sensitive to fluctuations in the concentration of oxygen (O2), on which they depend to generate adenosine triphosphate (ATP), the cell’s source of energy. O2 deprivation (anoxia) causes a reduction in oxidative phosphorylation and a corresponding decrease in ATP, which is most acutely experienced in organs with high metabolic demand, such as the brain, heart and kidney. However, it has been documented that some organisms can respond to low O2 with a programmed transition into a “suspended” or hypometabolic state, characterized by a dramatic reduction in ATP consumption via arrest of ATP-dependent processes. This condition has a protective effect on organism viability and is reversible, allowing the organism to resume metabolism and life once O2 is restored. Understanding how to trigger such a hypometabolic state could have dramatic consequences for the prevention of hypoxic/ischemic injury and to promote the viability and storage of organs for transplantation. The zebrafish represents an outstanding model for studying the regulation of hypometabolism. Depending on the stage, embryos exposed to anoxia can arrest development for up to 50 hours and then successfully produce viable adults once O2 is restored. The premise of this proposal is that the identification of key signaling molecules that trigger anoxia-induced arrest in the zebrafish embryo will further our understanding of this process and provide therapeutic targets for protecting patients from hypoxic/ischemic injury. We hypothesize that the metabolite lactate acts as a cellular signal for reduced O2, and triggers metabolic arrest through stabilization and translocation of N-myc Downstream Regulated (NDRG) proteins that block ATP-demanding processes. We will reveal the role of lactate/NDRG1 signaling in adaptation to reduced O2 by pursuing three aims: (1) Test whether lactate/NDRG1 signaling is important for developmental arrest, (2) Investigate the role of lactate in post-translational regulation of NDRG1, (3) Investigate the role of lactate/NDRG1 in arresting the Na+K+ATPase pump.

提案摘要 大多数生物体对氧气（O2）浓度的波动高度敏感， 依赖于产生三磷酸腺苷（ATP），细胞的能量来源。缺氧 （缺氧）导致氧化磷酸化的减少和ATP的相应减少， 在具有高代谢需求的器官中，如大脑、心脏和 肾然而，已经有文献证明，一些生物体可以对低O2做出反应， 程序性转变为“暂停”或低代谢状态，其特征在于 通过抑制ATP依赖性过程减少ATP消耗。这种情况具有保护性 对生物体活力的影响是可逆的，允许生物体恢复新陈代谢和生命 一旦氧气恢复了解如何触发这种低代谢状态可能会有戏剧性的 预防缺氧/缺血性损伤的后果，并促进细胞的活力和储存， 器官移植。斑马鱼代表了一个杰出的模型，用于研究 低代谢根据不同的阶段，暴露于缺氧的胚胎可以阻止发育， 长达50小时，然后一旦氧气恢复，就能成功生产出可存活的成虫。此前提 建议是，识别触发缺氧诱导的心脏骤停的关键信号分子， 斑马鱼胚胎将进一步加深我们对这一过程的理解，并为人类提供治疗靶点。 保护患者免受缺氧/缺血性损伤。我们假设代谢物乳酸作为一种 减少O2的细胞信号，并通过稳定和转运 N-myc下游调节（NDRG）蛋白质，阻止ATP需求过程。我们就会揭开 乳酸/NDRG 1信号传导在适应减少的O2中的作用，通过追求三个目标：（1）测试 乳酸/NDRG 1信号传导是否对发育停滞很重要，（2）研究乳酸/NDRG 1信号传导的作用。 乳酸在NDRG 1翻译后调控中的作用;（3）探讨乳酸/NDRG 1在NDRG 1翻译后调控中的作用 抑制了Na+K+ ATP酶的泵。