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

描述（由申请人提供）：心脏病是工业化国家的主要死因。心肌梗死后的生存率已显着提高，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增加。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导调节剂的作用已得到证实，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，我们将研究PGC-1a在心脏疾病中的作用。首先，我们将通过在缺乏PGC-1a的小鼠中使用横向主动脉缩窄（TAG）来测试PGC-1a的缺失是否会加重心力衰竭。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，我们也会问心力衰竭的发展是否可以通过心脏中PGC-1a的温和转基因表达来改善。我们还表明，在初步的数据中，PGC-1a通过表达广泛的ROS解毒基因在抑制活性氧（ROS）中起着关键作用。认为心脏中的缺血/再灌注损伤在很大程度上通过ROS的产生损害心脏。我们将使用获得或失去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，这些突变等位基因选择性地失去调节ATP产生系统或ROS解毒程序的能力。将在组织培养环境中评价这些等位基因，然后将其敲入小鼠生殖系，并检查对心脏的后续影响。这项拟议的工作，结合起来，应该批判性地评估PGC-1通路影响和改善主要形式的心脏病的能力。这可能导致一类新疗法的发展。

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.