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

描述（由申请人提供）：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治疗这些使人衰弱的疾病提供新的治疗方法。我们之前的研究表明，内质网（ER）应激的增加和未折叠蛋白反应（UPR）信号通路的激活在肥胖患者的胰岛素抵抗和2型糖尿病的发展中起着核心作用。UPR信号主要通过IRE1介导的c-Jun氨基末端激酶1 （JNK1）的激活和IRS-1丝氨酸307位点的磷酸化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在一个复合体中相关，因此任何一个基因的缺乏都会破坏该复合体的功能，并导致哺乳动物雷帕霉素靶蛋白（mTOR）复合体1 （mTORC1）的不受控制和异常激活。mTORC1通路的过度活跃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。胰岛素刺激的IRS1和IRS2的激活在TSC1-/-和TSC2-/-细胞中被完全阻断，同时IRS蛋白降解增加。然而，负责阻断IRS活性和增强降解的分子机制尚不清楚。我们的初步数据显示，缺乏TSC1或TSC2，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。通过化学伴侣4-苯基丁酸（4- pba）阻断内质网应激，显著改善胰岛素信号传导并完全阻断ir -1降解，表明UPR在tsc缺乏症胰岛素抵抗的发展中发挥重要作用。我们的建议是基于这些发现，旨在研究JNK-1和IRS-1ser307磷酸化在tsc1缺乏肝脏胰岛素抵抗发展中的体内作用。

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.