Molecular mechanisms dictating Sirt1/HIF-2 signaling during hypoxia

缺氧期间Sirt1/HIF-2信号传导的分子机制

• 批准号: 8195371
• 负责人: Joseph Anthony Garcia
• 金额: $ 30.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195371
• 关键词: Ablation; Acetylation; Acetyltransferase; Acute; Adult; Affect; Aging; Animal Model; Antioxidants; Biological; Biology; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cellular Stress; Characteristics; Complex; Data; Deacetylase; Disease; EP300 gene; Enzymes; Erythropoietin; Eukaryota; Exposure to; Family; Feedback; Gene Expression; Genes; Genetic; Genotoxic Stress; Goals; Heart; Hypoxia; Hypoxia Inducible Factor; Ischemia; Knowledge; Life; Link; Malignant Neoplasms; Mammals; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardium; NADH; Nature; Organism; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pharmaceutical Preparations; Physiological; Physiology; Play; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; Stroke; Testing; Therapeutic Agents; Tissues; Tube; United States; Vertebrates; bHLH-PAS factor HLF; base; biological adaptation to stress; cell killing; design; detection of nutrient; disability; human disease; hypoxia inducible factor 1; member; mortality; novel; novel therapeutics; preconditioning; research study; response; transcription factor

DESCRIPTION (provided by applicant): The ability to recognize and respond to environmental stress is an essential characteristic of all living organisms. A low oxygen state, or hypoxia, is an environmental stress encountered under physiological as well as pathophysiological disease states such as myocardial infarction and stroke. In higher eukaryotes, the cell-intrinsic transcriptional hypoxia response includes actions mediated by Hypoxia Inducible Factor (HIF) transcription factors. In vertebrates, the HIF family is comprised of three members with HIF-1 and HIF-2 being essential for survival as indicated by results from genetic ablation studies in mice. Despite their similarity at the protein level, HIF-1 and HIF-2 have distinct biological roles. HIF-2 is the specific HIF factor responsible for induction of erythropoietin and of major antioxidant enzymes (AOE) in adult mice, thereby regulating cell survival and protective cellular responses against oxidative stress, respectively. We recently demonstrated that HIF-2, but not HIF-1, signaling during hypoxia is selectively augmented by Sirtuin 1 (Sirt1), a deacetylase also implicated in aging, nutrient sensing, and genotoxic stress response. Our central hypothesis is that Sirt1/HIF-2 signaling is an essential signaling pathway for protection against hypoxia-induced damage in mammals. Preliminary data within this proposal reveal that Sirt1 levels increase during hypoxia, HIF-2 is acetylated by specific cellular acetyltransferases during hypoxia, and cardiomyocyte-specific HIF-2 ablation in mice results in worse outcome following myocardial infarction. The experiments proposed are aimed at elucidating the mechanism and biological role for Sirt1/HIF-2 signaling in mammals using test tube, cell culture, and animal model studies. Our long-term goals are to identify the prosurvival mechanisms activated during hypoxia and to leverage this knowledge to develop novel therapeutic agents for treatment of myocardial infarction and stroke, the leading causes of morbidity and mortality in US adults today. The Specific Aims of this proposal are as follows: Aim 1: Define the role of HIF signaling in Sirt1 activation during hypoxia Aim 2: Define the role of acetylation in Sirt1/HIF-2 signaling Aim 3: Define the role of HIF-2 in cardiac physiology after myocardial infarction PUBLIC HEALTH RELEVANCE: A low oxygen level is a major feature of several human diseases including heart attack, stroke, and cancer. When faced with this stress, cells in our body respond by turning on genes in an attempt to survive. Understanding how this response is controlled will allow us to design new drugs that will save cells (as desired after a heart attack or stroke) or to kill cells (as desired in the case of cancer).

描述(由申请人提供)：识别和应对环境压力的能力是所有生物的基本特征。低氧状态，或低氧，是一种在生理和病理生理疾病状态下遇到的环境应激，如心肌梗死和中风。在高等真核生物中，细胞固有的转录低氧反应包括由低氧诱导因子(HIF)转录因子介导的作用。在脊椎动物中，HIF家族由三个成员组成，小鼠的遗传消融研究结果表明，HIF-1和HIF-2是生存所必需的。尽管HIF-1和HIF-2在蛋白质水平上相似，但它们具有不同的生物学作用。HIF-2是诱导成年小鼠促红细胞生成素和主要抗氧化酶(AOE)的特异性HIF因子，从而分别调节细胞存活和保护细胞对氧化应激的反应。我们最近证明，Sirtuin 1(Sirt1)选择性地增强了缺氧过程中的HIF-2信号，而不是HIF-1信号。Sirt1是一种脱乙酰酶，也与衰老、营养感知和遗传毒性应激反应有关。我们的中心假设是Sirt1/HIF-2信号通路是保护哺乳动物免受缺氧损伤的重要信号通路。该方案的初步数据显示，Sirt1水平在低氧期间增加，HIF-2在低氧期间被特定的细胞乙酰转移酶乙酰化，而小鼠心肌细胞特异性HIF-2的消融会导致心肌梗死后更糟糕的预后。这些实验旨在通过试管、细胞培养和动物模型研究来阐明Sirt1/HIF-2信号在哺乳动物中的机制和生物学作用。我们的长期目标是确定在低氧期间激活的生存机制，并利用这一知识开发用于治疗心肌梗死和中风的新型治疗剂，这两种疾病是当今美国成年人发病率和死亡率的主要原因。该方案的具体目的如下：目标1：确定缺氧时Sirt1激活中HIF信号的作用目标2：确定乙酰化在Sirt1/HIF-2信号中的作用目标3：确定HIF-2在心肌梗死后心脏生理中的作用 与公共卫生相关：低氧水平是包括心脏病发作、中风和癌症在内的几种人类疾病的主要特征。当面对这种压力时，我们体内的细胞会通过启动基因来做出反应，试图生存下来。了解这种反应是如何控制的，将使我们能够设计新的药物来拯救细胞(如心脏病发作或中风后所需)或杀死细胞(如癌症所需)。