A Stress Inducible Protein Sestrin2 in Heart Failure

心力衰竭中的应激诱导蛋白 Sestrin2

• 批准号: 10363811
• 负责人: Ji Li
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363811
• 关键词: AMP-activated protein kinase kinase; Address; Adult; Adverse effects; Aging; Agonist; Antioxidants; Basic Science; Binding; Cardiac; Cardiac Myocytes; Caring; Cause of Death; Chronic Obstructive Pulmonary Disease; Clinical; Complex; Congestive Heart Failure; Coronary; Data; Dependovirus; Development; Devices; Diabetes Mellitus; Diagnosis; FRAP1 gene; Glucose; Goals; Healthcare Systems; Heart; Heart Hypertrophy; Heart failure; Homeostasis; Hospitalization; Hypertension; Hypertrophy; Impairment; Inflammatory; Knock-out; Laboratories; Left Ventricular Hypertrophy; Mediating; Mediator of activation protein; Medical center; Metabolic; Metabolism; Microvascular Dysfunction; Molecular; Mus; Obesity; Outcome Study; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population; Pre-Clinical Model; Prevalence; Prevention; Promoter Regions; Proteins; Provider; Publishing; Regulation; Reporting; Research; Resources; Response Elements; Rest; Risk Factors; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Sirolimus; Stress; Symptoms; Testing; Tetanus Helper Peptide; Time; Transgenic Mice; Translational Research; Treatment Failure; Ventricular Remodeling; Veterans; Work; age related; antagonist; cardiogenesis; comorbidity; cost; disability; experimental study; fatty acid metabolism; heart function; hypertensive; improved; military veteran; new therapeutic target; novel; older patient; overexpression; pressure; prevent; provider networks; response; sensor; synergism; transcription factor

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.

心力衰竭是一个日益普遍的问题，尤其是在老年退伍军人中 人口。从临床角度来看，肥胖、糖尿病等合并症的患病率 这些患者的慢性阻塞性肺病（COPD）、衰老和高血压导致了 炎症假说认为心力衰竭也与冠状动脉微血管功能障碍有关。 然而，适应不良的底物代谢和冠状动脉血流受损的因果关系 心力衰竭发展中的调控仍不清楚。本提案中描述的工作 将基础研究和转化研究水平的实验结合起来，以满足我们的迫切需求 退伍军人寻求新颖有效的心力衰竭疗法。我们研究的长期目标是 了解压力诱导因子 Sestrin2 (Sesn2) 作用的分子机制 蛋白质，介导从代偿性左心室肥大到失代偿性左心室肥厚的进展 心力衰竭中的肥厚和适应不良的心室重塑。我们已经证明 Sesn2 是 生理性和病理性心脏肥大的介质，现在正在寻求定义 潜在的分子机制。 Sesn2 敲除 (Sesn2 KO) 小鼠在 与野生型（WT）同窝小鼠相比，它们可以休息，但容易出现病理性肥大 压力过载。此外，我们实验室最近发布的数据表明 Sesn2 作为年龄- 调节 AMPK（一种心脏能量传感器）的相关蛋白，以维持代谢稳态 压力条件。与衰老相关的心力衰竭可能是由于 Sesn2-AMPK 信号级联受损所致 与高血压的不利影响协同发生。因此，我们的中心假设是 Sesn2 作为一种支架蛋白，在高血压引起的老年心力衰竭中发挥关键作用。目标 1： 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 信号传导抑制高血压诱发的心力衰竭的发展 老化。目标 2：确定 Sesn2-mTORC1 复合物在高血压心脏反应中的作用 和老化。我们的长期目标是通过开发一种方法来改善患有心力衰竭的退伍军人的护理 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。