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

描述（由申请人提供）：心脏病是工业化世界的主要死亡原因。心肌梗死后的生存率有了很大的提高，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的患病率急剧上升。衰竭的心脏表现出许多能量异常，包括转录辅激活因子PGC-1a的表达减少。PGC-1a作为线粒体生物发生和呼吸的主要调节因子的作用已被证实，这表明该分子可能是心力衰竭的关键控制点，并开辟了新的治疗方法。我们和其他人已经证明PGC-1a -/-小鼠具有重要的生理心脏异常。在这里，我们将探讨PGC-1a在心脏病中的作用。首先，我们将通过在缺乏PGC-1a的小鼠中使用横断主动脉收缩（TAG）来测试PGC-1a的缺失是否会加剧心力衰竭。初步数据显示PGC-1a缺失时心力衰竭严重恶化。反过来，我们也会问是否可以通过在心脏中温和的转基因表达PGC-1a来改善心力衰竭的发展。我们还在初步数据中表明，PGC-1a通过表达广泛的活性氧解毒基因，在抑制活性氧（ROS）中发挥关键作用。心脏缺血/再灌注损伤被认为在很大程度上是通过ROS的产生来损害心脏的。我们将使用PGC-1a缺失或增加的小鼠来评估这种共激活物在心脏缺血/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通过产生这种共激活因子的突变等位基因来发挥心脏保护作用的机制，这种突变等位基因选择性地失去了调节ATP产生系统或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，然后敲入小鼠生殖系，并检查对心脏的后续影响。总的来说，这项拟议的工作应该批判性地评估PGC-1途径影响和可能改善主要形式心脏病的能力。这可能会导致一类新的治疗方法的发展。

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.