Characterization of human IRS-1 Phosphorylation at S348, T495, and S1005

人类 IRS-1 S348、T495 和 S1005 磷酸化的表征

• 批准号: 7535489
• 负责人: Paul R Langlais
• 金额: $ 5.13万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2009-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535489
• 关键词: Condition; Disease; Goals; Health Care Costs; Human; Individual; Insulin; Insulin Receptor; Insulin Resistance; Knowledge; Laboratories; Mass Spectrum Analysis; Mediating; Metabolic syndrome; Mission; Modality; Molecular; Molecular Target; Molecular Weight; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pattern; Phosphorylation; Phosphorylation Site; Phosphotransferases; Prevention; Proteins; Public Health; Purpose; Regulation; Research; Serine; Serine/Threonine Phosphorylation; Signaling Protein; Site; Skeletal Muscle; Techniques; Testing; Threonine; Threonine Phosphorylation Site; Tissues; Tyrosine; Tyrosine Phosphorylation; basal insulin; base; diabetic; human FRAP1 protein; human subject; in vivo; insight; insulin receptor substrate 1 protein; protein function; research study; volunteer

DESCRIPTION (provided by applicant): Research in our laboratory focuses on the mechanisms of insulin resistance in human skeletal muscle. Specifically, we ask how serine/threonine phosphorylation of the signaling protein IRS-1 modulates the function of this protein, which is a key to insulin action in muscle. Using sensitive mass spectrometry techniques, we identified 22 serine/threonine phosphorylation sites in IRS-1 isolated from human vastus lateralis muscle. We quantified the effect of insulin on the in vivo phosphorylation of 15 of these residues. Of these 15 sites, phosphorylation of 4 residues, Ser348, Thr446, Thr495, and Ser1005, was decreased upon insulin treatment. The purpose of this proposal is to provide support for Dr. Langlais to ascertain whether the insulin controlled pattern and level and of phosphorylation of Ser348, Thr446, Thr495, and Ser1005 in human IRS-1 is deregulated in obese and type 2 diabetic human subjects as compared to lean, healthy controls. The second aim of this proposal is to identify the kinase(s) responsible for their phosphorylation, with mTOR being the principal candidate kinase. These experiments will provide a conceptual framework in which to place into context other results from our laboratory regarding regulation of phosphorylation of these sites in human muscle in vivo. Therefore Dr. Langlais' experiments will interweave with the larger mission of the laboratory. Definition of the molecular mechanisms responsible for insulin resistance will provide knowledge regarding the pathogenesis of type 2 diabetes mellitus and potentially provide molecular targets for treatment modalities. PUBLIC HEALTH RELEVANCE: Understanding how insulin fails to function properly in its target tissues, such as skeletal muscle, will provide insight into how individuals develop insulin resistance, type 2 diabetes, obesity, and the metabolic syndrome. Since these diseases are a growing public health problem responsible together for about 40% of public health costs, knowledge of the origins prevention and potential treatments for these diseases are imperative.

描述（由申请人提供）：我们实验室的研究重点是人类骨骼肌胰岛素抵抗的机制。具体来说，我们询问信号蛋白 IRS-1 的丝氨酸/苏氨酸磷酸化如何调节该蛋白的功能，这是肌肉中胰岛素作用的关键。使用灵敏的质谱技术，我们在从人股外侧肌中分离出的 IRS-1 中鉴定出了 22 个丝氨酸/苏氨酸磷酸化位点。我们量化了胰岛素对其中 15 个残基体内磷酸化的影响。在这 15 个位点中，4 个残基（Ser348、Thr446、Thr495 和 Ser1005）的磷酸化在胰岛素治疗后降低。该提案的目的是为 Langlais 博士提供支持，以确定与瘦健康对照相比，肥胖和 2 型糖尿病人类受试者中胰岛素控制模式和水平以及人 IRS-1 中 Ser348、Thr446、Thr495 和 Ser1005 的磷酸化是否失调。该提案的第二个目标是确定负责磷酸化的激酶，其中 mTOR 是主要候选激酶。这些实验将提供一个概念框架，将我们实验室关于人体肌肉体内这些位点磷酸化调节的其他结果置于背景中。因此，朗格莱斯博士的实验将与实验室更大的使命交织在一起。胰岛素抵抗分子机制的定义将提供有关 2 型糖尿病发病机制的知识，并可能为治疗方式提供分子靶点。 公共健康相关性：了解胰岛素如何无法在其靶组织（例如骨骼肌）中正常发挥作用，将有助于深入了解个体如何发展胰岛素抵抗、2 型糖尿病、肥胖和代谢综合征。由于这些疾病是一个日益严重的公共卫生问题，约占公共卫生成本的 40%，因此了解这些疾病的起源预防和潜在治疗方法势在必行。