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

描述(申请人提供)：肥胖是胰岛素抵抗和2型糖尿病发展的主要潜在病理之一。了解导致胰岛素抵抗和2型糖尿病的分子机制可以为这些衰弱疾病的治疗提供新的治疗方法。我们先前已经证明，内质网(ER)压力增加和未折叠蛋白反应(UPR)信号通路的激活在肥胖的胰岛素抵抗和2型糖尿病的发生中起核心作用。UPR信号主要通过肌醇需要酶-1(IRE1)介导c-jun氨基末端激酶-1(JNK1)的激活以及随后IRS-1在丝氨酸307处的磷酸化而导致胰岛素抵抗的发生。结节性硬化症复合体1和2(TSC1和2)基因都编码肿瘤抑制因子。TSC1和TSC2在一个复合体中存在，其中任何一个基因的缺失都会破坏该复合体的功能，导致哺乳动物雷帕霉素靶标(MTOR)复合体1(MTORC1)的失控和异常激活。MTORC1途径的过度激活会导致严重的胰岛素抵抗。这在缺乏TSC1或TSC2的细胞中最为明显。在TSC1-/-和TSC2-/-细胞中，胰岛素刺激的IRS1和IRS2的激活被完全阻断，同时增加了IRS蛋白的降解。然而，对IRS活性的阻断和加速降解的分子机制却知之甚少。我们的初步数据显示，TSC1或TSC2的缺失，以及随之而来的mTORC1通路的过度活跃，导致内质网应激，并激活UPR。化学伴侣4-苯基丁酸(4-PBA)阻断内质网应激，显著改善胰岛素信号转导，并完全阻断IRS-1的降解，表明UPR在TSC缺乏时胰岛素抵抗的发生发展中起重要作用。我们的建议基于这些发现，旨在研究体内JNK-1和IRS-1ser307磷酸化在TSC1缺陷肝脏胰岛素抵抗形成中的作用。 肥胖是一个快速增长的问题，是21世纪对人类健康最严重的威胁之一。肥胖是发展为胰岛素抵抗的最高风险。胰岛素抵抗使受影响的个体容易患上各种疾病，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寻找新的治疗机会至关重要。我们的建议，通过使用基因工程小鼠模型，旨在研究胰岛素抵抗的分子机制。

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.