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）：心脏病是工业化国家的首要死因。心肌梗塞后的生存率已大大提高，但缺血/再灌注损伤等急性损伤以及高血压和糖尿病等慢性损伤后的心脏重塑导致心力衰竭患病率急剧增加。衰竭的心脏表现出许多能量异常，包括转录共激活因子 PGC-1a 表达减少。 PGC-1a 作为线粒体生物发生和呼吸的主要调节剂的作用已得到证实，表明该分子可能代表心力衰竭的关键控制点并开辟新的治疗方法。我们和其他人已经证明 PGC-1a -/- 小鼠具有重要的生理性心脏异常。在这里，我们将研究 PGC-1a 在心脏病中的作用。首先，我们将通过对缺乏 PGC-1a 的小鼠进行主动脉横缩术 (TAG) 来测试 PGC-1a 的缺失是否会加剧心力衰竭。初步数据表明，缺乏 PGC-1a 时心力衰竭会严重恶化。相反，我们还将询问是否可以通过心脏中 PGC-1a 的轻度转基因表达来改善心力衰竭的发展。我们还在初步数据中表明，PGC-1a 通过表达广泛的 ROS 解毒基因程序，在抑制活性氧 (ROS) 方面发挥着关键作用。心脏缺血/再灌注损伤被认为在很大程度上是通过活性氧的产生来损害心脏的。我们将使用获得或丢失 PGC-1a 的小鼠来评估这种共激活剂在心脏缺血/再灌注损伤中的作用。分析将在分子和功能水平上进行。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发挥心脏保护作用的机制，这些突变等位基因选择性地失去调节 ATP 生成系统或 ROS 解毒程序的能力。这些等位基因将在组织培养环境中进行评估，然后敲入小鼠种系，并检查随后对心脏的影响。综上所述，这项拟议的工作应该严格评估 PGC-1 通路影响并可能改善主要形式的心脏病的能力。这可能会导致一类新疗法的开发。