PGC-1a and the Energetics of Heart Function and Disease

PGC-1a 与心脏功能和疾病的能量学

• 批准号: 7258256
• 负责人: BRUCE M. SPIEGELMAN
• 金额: $ 47.38万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-16 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258256
• 关键词: Acute; Address; Alleles; Animals; Biogenesis; Cardiac; Cause of Death; Chronic; Class; Clinical; Congenital Heart Defects; Constriction procedure; Cultured Cells; Data; Development; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Event; Experimental Models; Functional disorder; Generations; Genes; Germ Lines; Heart; Heart Diseases; Heart failure; Hypertension; Knock-in Mouse; Lead; Lesion; Mediating; Mitochondria; Modeling; Molecular; Mus; Myocardial Infarction; Outcome; Oxidative Phosphorylation; Pathway interactions; Physiological; Play; Prevalence; Process; Rattus; Reactive Oxygen Species; Reperfusion Injury; Respiration; Role; System; Testing; Therapeutic; Thinking; Tissues; Transcription Coactivator; Transgenic Organisms; Wild Type Mouse; Work; heart function; improved; inorganic phosphate; mortality; mutant; novel therapeutics; pressure; prevent; programs; tissue culture

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in the industrialized world. Survival after myocardial infarction has improved considerably, but the cardiac remodeling that follows acute insults like ischemia/reperfusion injuries and chronic ones like hypertension and diabetes has led to a dramatic increase in the prevalence of heart failure. The failing heart displays numerous energetic abnormalities, including decreased expression of the transcriptional coactivator PGC-1a. The proven role of PGC-1a as a dominant regulator of mitochondrial biogenesis and respiration suggests that this molecule could represent a key control point for heart failure and open new therapeutic approaches. We and others have shown that PGC-1a -/- mice have important physiological cardiac abnormalities. Here, we will investigate the role of PGC-1a in cardiac disease. First, we will test if loss of PGC-1a exacerbates heart failure, by using transverse aortic constriction (TAG) in mice lacking PGC-1a. Preliminary data indicates a severe worsening of heart failure in the absence of PGC-1a. Conversely, we will also ask whether the development of heart failure can be ameliorated by mild, transgenic expression of PGC-1a in the heart. We also show in preliminary data that PGC-1a plays a key role in the suppression of reactive oxygen species (ROS) through expression of a broad program of ROS detoxification genes. Ischemia/reperfusion injury in the heart is thought to damage the heart in large part via generation of ROS. We will evaluate, using mice with gain or loss of PGC-1a, the role of this coactivator in ischemia/reperfusion injury in the heart. Analysis will be at both molecular and functional levels. Lastly, we will examine in detail the mechanisms by which PGC-1a plays a cardioprotective role by creating mutant alleles of this coactivator that selectively lose the ability to modulate either the ATP producing system or the ROS detoxification program. These alleles will be evaluated in a tissue culture setting and then knocked into the murine germline, and the subsequent effects on the heart will be examined. This proposed work, taken together, should critically evaluate the ability of the PGC-1 pathway to influence and perhaps ameliorate major forms of heart disease. This may lead to the development of a new class of therapeutics.

描述（由申请人提供）：心脏病是工业化世界中死亡的主要原因。心肌梗塞后的生存率大大提高，但是诸如缺血/再灌注损伤之类的急性损伤之后的心脏重塑以及高血压和糖尿病等慢性损伤导致心力衰竭患病的急剧增加。失败的心脏表现出许多能量异常，包括转录共激活因子PGC-1A的表达降低。 PGC-1A作为线粒体生物发生和呼吸的主要调节剂的可靠作用表明，该分子可以代表心力衰竭的关键控制点和开放新的治疗方法。我们和其他人表明，PGC-1A - / - 小鼠具有重要的生理心脏异常。在这里，我们将研究PGC-1A在心脏病中的作用。首先，我们将通过在缺乏PGC-1A的小鼠中使用横向主动脉收缩（TAG）来测试PGC-1A是否会加剧心力衰竭。初步数据表明，在没有PGC-1A的情况下，心力衰竭严重恶化。相反，我们还将询问是否会通过心脏中PGC-1A轻度转基因表达来改善心力衰竭的发展。我们在初步数据中还显示，PGC-1A通过表达广泛的ROS解毒基因程序来抑制活性氧（ROS）在抑制中起关键作用。人们认为，心脏缺血/再灌注损伤被ROS的产生很大程度上会损害心脏。我们将使用PGC-1A的增益或损失的小鼠评估该共激活因子在缺血/再灌注损伤中的作用。分析将在分子水平和功能水平上。最后，我们将详细研究PGC-1A通过创建该共激活因子的突变等位基因来选择性地失去调节ATP产生系统或ROS ROS解毒程序的能力，从而详细研究PGC-1A发挥心脏保护作用的机制。这些等位基因将在组织培养环境中进行评估，然后将其撞到鼠种系中，并将检查对心脏的后续影响。这项提出的工作共同评估了PGC-1途径影响甚至改善心脏病的主要形式的能力。这可能会导致新的治疗疗法的发展。