Skeletal Muscle and Brown Adipose Mechanisms Mediating Cardiovascular Risk Factor Protection in RGS14 KO

RGS14 KO 中骨骼肌和棕色脂肪机制介导心血管危险因素保护

• 批准号: 9900047
• 负责人: STEPHEN F VATNER
• 金额: $ 53.43万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900047
• 关键词: Adipose tissue; Aging; Brown Fat; Caloric Restriction; Cardiac Death; Clinical; Country; Data; Development; Diabetes Mellitus; Diet; Disease; Energy Metabolism; Epidemic; Excision; Fatty acid glycerol esters; Female; GTP-Binding Protein Regulators; GTP-Binding Proteins; Genetic; Glucose; Glucose Intolerance; Goals; Health; Health Care Costs; Heart Diseases; Insulin Resistance; Knock-out; Knockout Mice; Longevity; Mediating; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Palate; Pathway interactions; Patients; Pharmacology; Population; SIRT1 gene; SOD2 gene; Signal Pathway; Signaling Protein; Skeletal Muscle; Specificity; Stress; Striated Muscles; Transplantation; Wild Type Mouse; aging population; base; cardiovascular risk factor; compliance behavior; dietary restriction; gender difference; glucose metabolism; improved; inhibitor/antagonist; male; novel; novel therapeutics; oxidation; protective effect

Project Summary: We have generated a mouse knockout (KO) of the regulator of G protein signaling 14 (RGS14). The RGS14 KO mice live longer than their wild type (WT) littermates and are protected against stress, type 2 diabetes and obesity, all features related to cardiovascular risk protection. The mechanisms mediating these salutary effects of the RGS14 KO involve the striated muscle. The RGS14 KO also has increased brown adipose tissue, which is likely involved in the mechanism of its protective effects. The goal of this proposal is to determine the mechanisms mediating these salutary actions. We plan to establish the RGS14 KO as a novel model for longevity and determine to what extent striated muscle specific loss of RGS 14 and brown adipose tissue contribute to longevity, and protection against obesity and diabetes. In this proposal “diabetes” is used to reflect protection of glucose utilization and insulin resistance, rather than the clinical disease. Our long term goal is to develop a clinically useful pharmacological inhibitor of RGS14. The proposal is based on the following hypotheses: Hypothesis A: Striated muscle specificity of RGS14 KO protects against the development of insulin resistance, glucose intolerance and obesity and extends lifespan mediated by increased energy metabolism through mitochondrial oxidation and protection against oxidative stress through the NAD+/SIRT3/MnSOD pathway. Hypothesis B: The RGS14 KO has the additional novel feature of increased brown adipose tissue, which also protects against diabetes, obesity and prolongs lifespan.

项目摘要： 我们已经产生了G蛋白信号转导调节因子14（RGS 14）的小鼠敲除（KO）。RGS14 KO 小鼠比它们的野生型（WT）同窝出生的小鼠活得更长，并且免受应激、2型糖尿病和 肥胖，所有与心血管风险保护相关的特征。调节这些有益效果的机制 RGS 14 KO的表达涉及横纹肌。RGS 14 KO还具有增加的棕色脂肪组织， 可能参与其保护作用的机制。本提案的目的是确定 调节这些有益行为的机制。我们计划建立RGS 14 KO作为长寿的新模型 并确定横纹肌特异性RGS 14和棕色脂肪组织的损失在多大程度上有助于 长寿，预防肥胖和糖尿病。在这一建议中，“糖尿病”被用来反映保护 葡萄糖利用和胰岛素抵抗，而不是临床疾病。 我们的长期目标是开发临床上有用的RGS 14药理学抑制剂。 该提案基于以下假设： 假设A：RGS 14 KO的横纹肌特异性防止胰岛素抵抗的发展， 葡萄糖耐受不良和肥胖，并通过增加能量代谢延长寿命， 通过NAD+/SIRT 3/MnSOD途径保护线粒体氧化和对抗氧化应激。 假设B：RGS 14 KO具有增加的棕色脂肪组织的额外新特征，其还 预防糖尿病、肥胖和延长寿命。