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.

项目概要： 我们已经对 G 蛋白信号传导调节因子 14 (RGS14) 进行了小鼠敲除 (KO)。 RGS14 KO 小鼠比同窝的野生型 (WT) 小鼠寿命更长，并且可以免受压力、2 型糖尿病和 肥胖，所有特征都与心血管风险保护相关。介导这些有益作用的机制 RGS14 KO 涉及横纹肌。 RGS14 KO 还增加了棕色脂肪组织，这 可能涉及其保护作用的机制。该提案的目标是确定 调解这些有益行动的机制。我们计划将 RGS14 KO 打造成一种新颖的长寿模型 并确定 RGS 14 和棕色脂肪组织的横纹肌特异性损失在多大程度上导致 长寿，预防肥胖和糖尿病。在该提案中，“糖尿病”用于反映对 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一种临床上有用的 RGS14 药理学抑制剂。 该提案基于以下假设： 假设 A：RGS14 KO 的横纹肌特异性可防止胰岛素抵抗的发展， 葡萄糖不耐受和肥胖，并通过增加能量代谢来延长寿命 通过 NAD+/SIRT3/MnSOD 途径抑制线粒体氧化和对抗氧化应激。 假设 B：RGS14 KO 具有增加棕色脂肪组织的额外新特征，这也 预防糖尿病、肥胖症并延长寿命。