A Stress Inducible Protein Sestrin2 in Heart Failure

心力衰竭是一个日益普遍的问题，尤其是在年迈的退伍军人中 人口。从临床的角度来看，肥胖、糖尿病、 COPD(慢性阻塞性肺疾病)、老龄化和高血压导致这些患者 炎症假说，心力衰竭也与冠脉微血管功能障碍有关。 然而，不适应底物代谢和冠状动脉血流受损的原因重要性 心力衰竭的发展过程中的调控尚不清楚。这份建议书中描述的工作 结合基础研究和翻译研究层面的实验，以满足我们的关键需求 新的有效的心力衰竭治疗的退伍军人。我们研究的长期目标是 了解压力诱导蛋白Sestrin2(Sesn2)作用的分子机制 蛋白质在左心室代偿性肥厚向失代偿期进展中的调节作用 心力衰竭患者的肥厚和适应性不良的心室重构。我们已经证明了Sesn2是 一种生理性和病理性心肌肥厚的介体，现在正在寻求定义 潜在的分子机制。Sesn2基因敲除(Sesn2 KO)小鼠在 与野生型(WT)产仔相比，REST容易出现病理性肥大 压力过载。此外，我们实验室最近公布的数据显示，Sesn2作为一个年龄- 调节AMPK的相关蛋白质，AMPK是心脏能量感受器，在 压力条件。衰老相关的心力衰竭可能是由于Sesn2-AMPK信号通路受损所致 与高血压的不良影响协同发生的。因此，我们的中心假设是Sesn2 作为一种支架蛋白，在高血压引起的衰老心力衰竭中发挥关键作用。目标1：实现 确定控制心脏Sesn2表达的上游信号通路及其机制 Sesn2介导的AMPK信号通路抑制高血压大鼠心力衰竭的研究 衰老。目的2：确定Sesn2-mTORC1复合体在高血压心脏反应中的作用 和衰老。我们的长期目标是通过发展一种 更好地了解导致心力衰竭的机制并确定新的靶向治疗方法 可以预防或逆转高血压性心力衰竭。

Heart failure is an increasingly prevalent problem and particularly so amongst an aging Veterans population. From a clinical standpoint, the prevalence of comorbid conditions such as obesity, diabetes, COPD (chronic obstructive pulmonary disease), aging and hypertension in these patients has led to the inflammatory hypothesis where heart failure is also associated with coronary microvascular dysfunction. Nevertheless, the causal importance of maladaptive substrate metabolism and impaired coronary flow regulation in the development of the heart failure remain unclear. The work described in this proposal combines experiments at the basic and translational research level to address the critical need of our veterans for novel and effective heart failure therapies. The long-term goal of our research is to understand the molecular mechanisms that underlie the role of Sestrin2 (Sesn2), a stress inducible protein, in mediating progression from compensated left ventricular hypertrophy to decompensated hypertrophy and maladaptive ventricular remodeling in heart failure. We have demonstrated that Sesn2 is a mediator of physiologic and pathologic cardiac hypertrophy and are now seeking to define the underlying molecular mechanisms. Sesn2 knockout (Sesn2 KO) mice display normal cardiac function at rest compared to wild type (WT) littermates but are vulnerable with pathologic hypertrophy in response to pressure overload. Furthermore, recently published data from our lab show that Sesn2 serves as an age- related protein that modulates AMPK, a cardiac energy sensor, to maintain metabolic homeostasis under stress conditions. Aging related heart failure could be due to impaired Sesn2-AMPK signaling cascade occurring in synergy with the adverse effects of hypertension. Thus, our central hypothesis is that Sesn2 serves as a scaffold protein that plays a key role in hypertension induced heart failure in aging. Aim 1: To determine the upstream signaling pathways that control cardiac Sesn2 expression, and the mechanisms by which Sesn2-mediated AMPK signaling inhibits development of hypertension-induced heart failure in aging. Aim 2: To determine the role of Sesn2-mTORC1 complex in the cardiac response to hypertension and aging. Our long-term objective is to improve the care of Veterans with heart failure by developing a better understanding of the mechanisms leading to heart failure and identifying novel targeted treatments that can prevent or reverse hypertensive heart failure.