Transcriptional/physiological analysis of cardiac HIF1

心脏 HIF1 的转录/生理分析

• 批准号: 7146754
• 负责人: Ralph V. Shohet
• 金额: $ 38.6万
• 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/7146754
• 关键词: Krebs' cycle; aging; angiogenesis; carbohydrates; gene expression; genetically modified animals; glycolysis; heart metabolism; histology; hypoxia; hypoxia inducible factor 1; laboratory mouse; long chain fatty acid; magnetic resonance imaging; myocardial infarction; myocardial ischemia /hypoxia; 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气传感分子。它是一个转录因子，受环境氧浓度对其稳定性的影响调节。 HIF1调节涉及低氧涉及的基因的综合基因，包括增加血管生成并有利于糖酵解代谢的因素。这些感兴趣的反应没有比心脏更大的反应，因为冠状动脉疾病引起的缺氧是发达国家发病率和死亡率的主要原因。因此，我们试图确定HIF1在心脏中的影响，以更好地了解内源性生理反应对缺氧。我们创建了一个转基因模型，其中HIF可以以受调节的心脏特异性方式表达。我们已经用不受氧气浓度影响的抗降解HIF1产生了转基因动物。我们的基本假设是，HIF1活性的心脏特异性升高将指导心脏概括低氧反应。我们的具体目的是使用分子，代谢和生理技术的结合来检验这一假设。具体目标1：确定体内HIF1转录激活的直接下游靶标。随着HIF1活性增加以捕获第一个响应并识别由HIF1调节的新基因，我们将对我们的模型进行全面的转录分析。具体目的2：测量特定生化途径对HIF1介导的从心脏中氧化转向糖酵解代谢的转换的贡献。这将通过自旋标记底物的磁共振光谱来完成。特定目的3：定义心脏中HIF1过表达的血管生成作用。这将需要组织学和生理分析，并将在缺氧和梗塞模型中进行探讨。