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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

基本信息

批准号：
8668131
负责人：
Joseph Anthony Garcia
金额：
$ 33.3万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668131
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

项目摘要

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

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体的基本特征。低氧状态或缺氧是在生理以及病理生理疾病状态（例如心肌梗塞和中风）下遇到的环境应激。在高等真核生物中，细胞内源性转录缺氧反应包括由缺氧诱导因子（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，其中HIF-1和HIF-2对于存活是必需的，如来自小鼠基因消融研究的结果所示。尽管它们在蛋白质水平上相似，但HIF-1和HIF-2具有不同的生物学作用。HIF-2是负责诱导成年小鼠中的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针对氧化应激的保护性细胞应答。我们最近证明，HIF-2，而不是HIF-1，信号在缺氧期间选择性增强Sirtuin 1（Sirt 1），脱乙酰酶也涉及衰老，营养传感和遗传毒性应激反应。我们的中心假设是，Sirt 1/HIF-2信号是一个重要的信号通路，保护对缺氧诱导的损伤哺乳动物。初步数据显示，Sirt 1水平在缺氧期间增加，HIF-2在缺氧期间被特定的细胞乙酰转移酶乙酰化，小鼠心肌细胞特异性HIF-2消融导致心肌梗死后预后更差。本实验旨在通过试管、细胞培养和动物模型研究来阐明哺乳动物中Sirt 1/HIF-2信号转导的机制和生物学作用。我们的长期目标是确定缺氧期间激活的促生存机制，并利用这些知识开发用于治疗心肌梗死和中风的新型治疗药物，心肌梗死和中风是当今美国成年人发病率和死亡率的主要原因。本研究的具体目的如下：目的1：明确缺氧时HIF信号通路在Sirt 1激活中的作用目的2：明确乙酰化在Sirt 1/HIF-2信号通路中的作用目的3：明确HIF-2在心肌梗死后心脏生理学中的作用