Restore energy capacity in the aging heart

线粒体在能量代谢和氧化还原调节中起着核心作用。超过了 过去十年，越来越多的证据表明， 线粒体功能障碍和与衰老相关的主要表型 组织，包括心脏。老化的心脏会出现心肌肥厚， 尤其是在机械压力下，如左心室压力超负荷时。 三磷酸腺苷合成酶是线粒体中产生三磷酸腺苷的关键酶复合体，因此在线粒体中发挥重要作用。 在线粒体功能中起中心作用。三磷酸腺苷合成酶功能缺陷可导致 加重人类疾病，如心肌病和充血性心力衰竭， 特别是在人口老龄化的情况下。然而，目前尚不清楚线粒体是否受损 三磷酸腺苷合成酶是能量缺乏的潜在机制之一。 老化心脏中的线粒体功能障碍。我们最近确定了一个PPAR目标 编码一种新的线粒体蛋白ES1的基因。初步研究表明，ES1 是一种线粒体蛋白，与三磷酸腺苷合成酶F1的α和β亚基相互作用 扇区。ES1似乎通过增加ATP的合成而促进了ATP的产生 和三磷酸腺苷水解酶的抑制剂。然而，目前仍不清楚ES1是否与ES1类似 调节心脏中的三磷酸腺苷的产生。有趣的是，我们的初步研究显示 14月龄小鼠心脏中的ES1蛋白水平降低。基于 在条件转基因和基因打靶小鼠品系的初步研究中，我们 假设ES1是保护心脏的新治疗靶点 与年龄相关的心肌病。为了检验这一中心假设，我们首先要确定 增加心脏ES1表达的基因治疗是否会保护心脏 与衰老相关的肥大。然后我们将定义潜在的分子和 通过确定ES1作为内源性调节因子的作用而实现的生化机制 ATP合酶和作为心脏线粒体结构/功能的决定因素。我们 预计拟议的研究将提供强有力的证据支持ES1是一种 心肌能量代谢的重要调节因子--三磷酸腺苷的调节作用 合酶与线粒体结构/功能。这项研究的结果将为临床前提供 ES1可以成为保护心脏免受衰老影响的新靶点的证据 肥大。

Mitochondria play a central role in energy metabolism and redox regulation. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging of various tissues, including the heart. The aging heart is subjected to cardiac hypertrophy, especially when under mechanical stress, such as left ventricular pressure overload. ATP synthase is a key enzyme complex generating ATP in mitochondria, thus playing a central role in mitochondrial function. Functional defects of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure, especially in aging population. However, it remains unclear if impaired mitochondrial ATP synthase is one of the underlying mechanism of energy deficiency and mitochondrial dysfunction in the aging heart. We have recently identified a PPAR-target gene encoding a novel mitochondrial protein ES1. Preliminary studies revealed that ES1 is a mitochondrial protein interacting with the subunits α and β of ATP synthase F1 sector. ES1 appears to be an enhancer of ATP production by increasing ATP synthesis and an inhibitor of ATP hydrolysis. However, it remains unknown if ES1 similarly regulates ATP production in the heart. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in the hearts from 14 month-old mice. Based on the pilot studies on conditional transgenic and gene targeting mouse lines, we hypothesize that ES1 is a novel therapeutic target of protecting the heart from aging-relating cardiomyopathy. To test this central hypothesis, we will first determine whether gene therapy that increasing cardiac ES1 expression will protect the heart from aging-related hypertrophy. We will then define the underlying molecular and biochemical mechanisms by determining the role of ES1 as an endogenous regulator of ATP synthase and as a determinant of mitochondrial structure/function in the heart. We anticipate the proposed study will provide strong evidence supporting that ES1 is a crucial regulator of myocardial energy metabolism via its regulatory effects on the ATP synthase and mitochondrial structure/function. Result of this study will provide preclinical evidence that ES1 can be a new target for protecting the heart from aging related hypertrophy.