Transcriptional and physiological analysis of cardiac HIF1

心脏 HIF1 的转录和生理分析

• 批准号: 7265288
• 负责人: Ralph V. Shohet
• 金额: $ 37.26万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265288
• 关键词: Affect; Age; Binding; Biochemical Pathway; Brain Hypoxia-Ischemia; Carbohydrates; Cardiac; Citric Acid Cycle; Coronary Arteriosclerosis; Degradation Pathway; Development; Elevation; Gene Expression; Genes; Glucose; Heart; Hypoxia; Infarction; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mutate; Oxygen; Physiological; Post-Translational Protein Processing; Production; Protein Binding; Protein Overexpression; Regulation; Resistance; Spin Labels; Stream; Techniques; Testing; Transcriptional Activation; Transgenic Animals; Transgenic Model; Transgenic Organisms; Vertebrates; anaerobic glycolysis; angiogenesis; hypoxia inducible factor 1; in vivo; interest; long chain fatty acid; mortality; myocardial hypoxia; novel; oxidation; research study; response; transcription factor

DESCRIPTION (provided by applicant): Hypoxia inducible factor-1 is a principal oxygen sensing molecule in all vertebrates. It is a transcription factor that is regulated by the effect of ambient oxygen concentration on its stability. HIF1 regulates a panoply of genes involved in response to hypoxia, including factors that augment angiogenesis and favor glycolytic metabolism. Nowhere are these responses of greater interest than in the heart, where hypoxia due to coronary artery disease is a major cause of morbidity and mortality in the developed world. We thus seek to determine the effects of HIF1 in the heart, to better understand the endogenous physiological response to hypoxia. We have created a transgenic model where HIF can be expressed in a regulated, cardiac-specific manner. We have generated our transgenic animal with a degradation-resistant HIF1 that is not affected by oxygen concentration. Our underlying hypothesis is that cardiac-specific elevation of HIF1 activity will direct the heart to recapitulate hypoxic responses. Our specific aims test this hypothesis using a combination of molecular, metabolic and physiological techniques. Specific Aim 1: To identify the immediate down-stream targets of HIF1 transcriptional activation in vivo. We will apply comprehensive transcriptional analysis to our model as HIF1 activity increases to catch the first response and identify novel genes that are regulated by HIF1. Specific Aim 2: To measure the contribution of specific biochemical pathways to the HIF1-mediated switch from oxidative to glycolytic metabolism in the heart. This will be accomplished with the magnetic resonance spectroscopy of spin-labeled substrates. Specific Aim 3: To define the angiogenic effects of HIF1 overexpression in the heart. This will require histological and physiological analysis and will be explored in models of hypoxia and infarction.

描述（由申请人提供）：缺氧诱导因子-1是所有脊椎动物中的主要氧敏感分子。它是一种转录因子，受环境氧浓度对其稳定性的影响调节。HIF 1调节一系列参与缺氧反应的基因，包括增强血管生成和促进糖酵解代谢的因子。没有什么比心脏更令人感兴趣的了，在发达国家，由于冠状动脉疾病引起的缺氧是发病率和死亡率的主要原因。因此，我们试图确定HIF 1在心脏中的作用，以更好地了解缺氧的内源性生理反应。我们已经建立了一个转基因模型，其中HIF可以以调节的心脏特异性方式表达。我们已经产生了我们的转基因动物与抗降解HIF 1不受氧气浓度的影响。我们的基本假设是心脏特异性HIF 1活性升高将指导心脏重演缺氧反应。我们的具体目标是使用分子，代谢和生理技术的组合来测试这一假设。具体目标1：确定体内HIF 1转录激活的直接下游靶点。随着HIF 1活性的增加，我们将对我们的模型应用全面的转录分析，以捕捉第一反应并识别受HIF 1调节的新基因。具体目标二：测量特定生化途径对心脏中HIF 1介导的从氧化代谢到糖酵解代谢的转换的贡献。这将通过自旋标记基底的磁共振光谱来实现。具体目标3：确定心脏中HIF 1过表达的血管生成作用。这将需要组织学和生理学分析，并将在缺氧和梗死模型中进行探索。