AS160 as a nodal regulator of the cardiac response to metabolic stress

AS160 作为心脏对代谢应激反应的节点调节器

• 批准号: 10674917
• 负责人: Sarah Marie Bass
• 金额: $ 56.32万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674917
• 关键词: ADRBK1 gene; Adipocytes; Adipose tissue; Adult; Adverse effects; Affect; American; Binding; Biological Markers; Biology; Body mass index; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Cardiovascular system; Cause of Death; Central obesity; Chronic; Co-Immunoprecipitations; Complex; Consensus; Country; Cues; Data; Diabetes Mellitus; Diet; Disease; Epidemic; Functional disorder; G protein coupled receptor kinase; GLUT 4 protein; Goals; Heart; Heart Diseases; Heart failure; High Fat Diet; Homeostasis; Human; Immunoprecipitation; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intervention Studies; Investigation; Knock-in; Knock-out; Knowledge; Left; Length; Life Style; Link; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolic stress; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Mutation; Myocardial dysfunction; N-terminal; Nodal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Peptides; Performance; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Protein Inhibition; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Regulation; Research; Respiration; Role; Sampling; Severity of illness; Signal Transduction; Skeletal Muscle; Stress; Stroke; Tertiary Protein Structure; Therapeutic Intervention; Tissue Sample; Translating; United States; Ventricular; Vesicle; Visualization; Woman; Work; abdominal fat; adipokines; atherosclerosis risk; cardiometabolism; cardioprotection; cardiovascular disorder risk; cardiovascular risk factor; crosslink; diet-induced obesity; driving force; flexibility; genetic risk factor; glucose uptake; heart function; heart metabolism; improved; inhibitor; insight; insulin receptor substrate 1 protein; insulin regulation; insulin sensitivity; insulin signaling; interest; knock-down; men; mortality; mouse model; negative affect; novel strategies; novel therapeutic intervention; obese person; preservation; pressure; recruit; response; small molecule; systemic inflammatory response; targeted treatment; therapeutic target; trafficking; uptake

PROJECT SUMMARY Heart disease is the leading cause of death for both men and women in the United States. Cardiovascular mortality rates positively correlate with the presence of diabetes, obesity and metabolic syndrome, which are rising in epidemic proportions and leading to poor outcomes including heart failure. There is a consensus that abdominal obesity is a major driving force in the pathogenesis of metabolic syndrome, with severe adverse effects on cardiovascular risk factors. In the midst of a growing recognition of how adipose tissue dysfunction and adipokine imbalance affect cardiac disease in the obese population, a less-well understood mechanism is the effect of cardiac metabolism and function on systemic metabolic homeostasis. In fact, little is known about the factors that link cardiac dysfunction and systemic metabolism. I have a long-standing interest in translational cardiovascular research, with previous investigations showing that elevated GRK2 activity and expression occurs early in disease and contributes to progression. Recently, my lab has shown that cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) is cardioprotective. Further, while GRK2 negatively affects insulin signaling through a direct interaction with and phosphorylation of insulin receptor substrate-1 (IRS1), βARKnt enhances activation of the insulin signaling pathway and mitochondrial efficiency. Our preliminary data also show that βARKnt reduces abdominal fat content and preserves systemic insulin responsiveness during high fat diet-induced obesity. Currently, we discovered selective interactions of endogenous GRK2 and βARKnt with Akt substrate of 160kDa (AS160). Pathway analysis of this proteomic data confirmed an AS160/GRK2 link and involved numerous regulators of insulin signaling. AS160 has been identified as nodal regulator between insulin signaling and glucose uptake, but research into its physiological role in cardiomyocyte metabolism has been hampered by limitations of available or selected models. We hypothesize that enhancing AS160 signaling in cardiomyocytes improves their metabolic flexibility in a cardioprotective manner and translates these to beneficial effects on systemic insulin responsiveness. Aim 1 will interrogate the physiological role of cardiac AS160 in insulin-stimulated GLUT4 membrane trafficking and the functional consequences for metabolite uptake and mitochondrial respiration in the heart. Aim 2 will elucidate the composition of the cardiac AS160 regulatory complex using cross-linking/mass spectrometry to visualize the components and their interactions in human left ventricular samples from patients with heart failure with or without diabetes compared to murine mimics of disease. These studies seek to fill important gaps in our knowledge regarding the composition of the cardiac AS160 regulatory complex, how it is altered during cardiometabolic stress, how it regulates cardiomyocyte metabolite utilization, and whether it translates this to influencing systemic metabolic performance. Our overall goal is to gain a better understanding of the regulation and relevance of AS160 in cardiomyocyte insulin- responsiveness and whether it represents a therapeutic target for cardiometabolic disease.

项目摘要 心脏病是美国男女死亡的主要原因。心血管 死亡率与糖尿病，肥胖和代谢综合征的存在正相关， 流行比例的增加，导致不良预后，包括心力衰竭。有一个共识 腹部肥胖是代谢综合征发病机理的主要驱动力，患有严重的逆境 对心血管危险因素的影响。在人们对脂肪组织功能障碍如何越来越认识到 脂肪因子不平衡会影响肥胖人群的心脏病，一种不太漏水的理解机制是 心脏代谢和功能对全身代谢稳态的影响。实际上，对 连接心脏功能障碍和全身代谢的因素。我对翻译有兴趣 心血管研究，先前的研究表明，GRK2活性和表达发生升高 早期疾病并有助于进展。最近，我的实验室表明心脏限制表达 GRK2（βARKNT）的简短的氨基末端碎片是心脏保护性的。此外，grk2负面影响 胰岛素信号通过与胰岛素受体底物-1（IRS1）， βARKNT增强了胰岛素信号通路和线粒体效率的激活。我们的初步数据 还表明βARKNT降低了腹部脂肪含量并保留全身胰岛素反应性 高脂饮食引起的肥胖症。目前，我们发现了内源性GRK2和βarknt的选择性相互作用 Akt基板为160KDA（AS160）。该蛋白质组学数据的途径分析证实了AS160/GRK2链接 并涉及许多胰岛素信号传导的调节剂。 AS160已被确定为淋巴结调节剂 胰岛素信号传导和葡萄糖吸收，但研究其在心肌细胞代谢中的身体作用具有 我们假设增强AS160信号传导 在心肌细胞中，以心脏保护方式改善其代谢灵活性，并将其转化为 对全身胰岛素反应的有益影响。 AIM 1将询问心脏的身体角色 AS160在胰岛素刺激的GLUT4膜运输和代谢产物摄取的功能后果 心脏中的线粒体呼吸。 AIM 2将阐明心脏AS160调节的组成 使用交联/质谱法来可视化组件及其在人左侧的相互作用的复合物 有或患有糖尿病患者的心力衰竭患者的心室样本与鼠模仿相比 疾病。这些研究旨在填补我们关于心脏组成的知识的重要空白 AS160调节络合物，在心脏代谢应力期间如何改变其调节方式，如何调节心肌细胞 代谢物利用率以及是否将其转化为影响系统的代谢性能。我们的整体 目标是更好地了解AS160在心肌细胞胰岛素中的调节和相关性 反应性及其是否代表心脏代谢疾病的治疗靶点。