The In Vivo Role of JNK-1 and IRS-1 Ser307 Phosphorylation In Development of Insu

JNK-1 和 IRS-1 Ser307 磷酸化在 Insu 发育中的体内作用

• 批准号: 8003722
• 负责人: Umut Ozcan
• 金额: $ 2.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003722
• 关键词: Adenoviruses; Adipose tissue; Affect; Back; Butyric Acids; Cardiovascular Diseases; Cell Line; Cell physiology; Cells; Chemicals; Complex; Data; Development; Disease; Endoplasmic Reticulum; Enzymes; Epidemic; Face; Feedback; Genes; Genetically Engineered Mouse; Growth; Health; Human; Hyperactive behavior; IRS2 gene; Incidence; Individual; Injection of therapeutic agent; Inositol; Insulin; Insulin Resistance; JUN gene; Knock-out; Liver; Mediating; Metabolism; Modality; Molecular; Molecular Chaperones; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathology; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Proteins; Role; Serine; Signal Pathway; Signal Transduction; TSC1 gene; TSC1/2 gene; TSC2 gene; Tail; Tuberous sclerosis protein complex; Tumor Suppressor Proteins; Tyrosine Phosphorylation; Veins; base; effective therapy; endoplasmic reticulum stress; feeding; high risk; improved; in vivo; insulin receptor serine kinase; insulin receptor substrate 1 protein; insulin signaling; mTOR protein; mouse model; novel therapeutic intervention; novel therapeutics; protein degradation; recombinase; response; sensor

DESCRIPTION (provided by applicant): Obesity is one of the major underlying pathologies for development of insulin resistance and type 2 diabetes. Understanding the molecular mechanisms leading to insulin resistance and type 2 diabetes can provide novel therapeutic approaches for treatment of these debilitating diseases. We have previously shown that increased endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) signaling pathways play a central role in development of insulin resistance and type 2 diabetes in obesity. UPR signaling leads to development of insulin resistance mainly through inositol requiring enzyme-1 (IRE1) mediated activation of c-Jun amino terminal Kinase-1 (JNK1) and consequent phosphorylation of IRS-1 at serine 307. Tuberous sclerosis complex 1 and 2 (TSC1 and 2) genes both encode tumor suppressors. TSC1 and TSC2 are associated in a complex such that deficiency of either gene disrupts the function of this complex, and leads to uncontrolled and aberrant activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Hyperactivity of mTORC1 pathway causes severe insulin resistance. This is most evident in cells lacking either TSC1 or TSC2. The insulin-stimulated activation of IRS1 and IRS2 is completely blocked in TSC1-/- and TSC2-/- cells together with increased IRS protein degradation. However, the molecular mechanisms responsible for blockade of IRS activity and enhanced degradation are poorly understood. Our preliminary data show that lack of TSC1 or TSC2, and consequent hyperactivity of mTORC1 pathway leads to ER stress and activates the UPR. Blockade of ER stress by a chemical chaperone, 4- phenyl butyric acid (4-PBA), significantly improves insulin signaling and completely blocks IRS-1 degradation, indicating that UPR plays an important role in development of insulin resistance in TSC-deficiency. Our proposal is based on these findings and aims to investigate the in vivo role of JNK-1 and IRS-1ser307 phosphorylation in development of insulin resistance in TSC1-deficient livers. Obesity is a fast growing problem and is one of the most serious threats to human health in the 21st century. Obesity constitutes the highest risk for development of insulin resistance. Insulin resistance predisposes the affected individuals to variety of diseases, including type 2 diabetes and cardiovascular disease. For this reason, understanding the underlying molecular mechanisms of insulin resistance is of crucial importance for new therapeutic opportunities. Our proposal, by using genetically engineered mouse models, aims to investigate the molecular mechanisms of insulin resistance.

描述（由申请人提供）：肥胖是胰岛素抵抗和2型糖尿病的发展的主要基础病理之一。了解导致胰岛素抵抗和2型糖尿病的分子机制可以提供新颖的治疗方法来治疗这些令人衰弱的疾病。我们先前已经表明，内质网应力增加，而展开的蛋白质反应（UPR）信号通路的激活在肥胖症中胰岛素抵抗和2型糖尿病的发展中起着核心作用。 UPR信号传导可导致胰岛素抵抗的发展主要是通过肌醇需要酶-1（IRE1）介导的C-Jun氨基末端激酶-1（JNK1）的激活，并在丝氨酸307上进行IRS-1的磷酸化307。 TSC1和TSC2与一个复合物相关联，使任何基因的缺乏都破坏了该复合物的功能，并导致雷帕霉素（MTOR）复合物1（MTORC1）的哺乳动物靶标的不受控制和异常激活。 MTORC1途径的多动症会引起严重的胰岛素抵抗。这在缺乏TSC1或TSC2的细胞中最明显。 IRS1和IRS2的胰岛素刺激的激活在TSC1 - / - 和TSC2 - / - 细胞中完全阻断，以及IRS蛋白质降解的增加。但是，对IRS活性阻断和增强降解的负责分子机制知之甚少。我们的初步数据表明，缺乏TSC1或TSC2，因此MTORC1途径的多动症导致ER应力并激活UPR。化学伴侣，4-苯基丁酸（4-PBA）对ER应激的阻断可显着改善胰岛素信号传导，并完全阻止IRS-1降解，表明UPR在TSC缺乏症中胰岛素抵抗的发展中起重要作用。我们的建议基于这些发现，并旨在研究JNK-1和IRS-1SER307磷酸化在TSC1缺陷型肝脏中胰岛素抵抗发展中的体内作用。 肥胖是一个快速发展的问题，是21世纪对人类健康最严重的威胁之一。肥胖是胰岛素抵抗发展的最高风险。胰岛素抵抗使受影响的个体患有多种疾病，包括2型糖尿病和心血管疾病。因此，了解胰岛素抵抗的潜在分子机制对于新的治疗机会至关重要。我们的建议通过使用基因工程的小鼠模型，旨在研究胰岛素抵抗的分子机制。