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
基本信息
- 批准号:7572946
- 负责人:
- 金额:$ 33.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-03-01 至 2012-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdenovirusesAdipose tissueAffectBackButyric AcidsCardiovascular DiseasesCell LineCell physiologyCellsChemicalsComplexDataDevelopmentDiseaseEndoplasmic ReticulumEnzymesEpidemicFaceFeedbackGenesGenetically Engineered MouseGrowthHealthHumanHyperactive behaviorIRS2 geneIncidenceIndividualInjection of therapeutic agentInositolInsulinInsulin ResistanceJUN geneKnock-outLiverMediatingMetabolismModalityMolecularMolecular ChaperonesMusNon-Insulin-Dependent Diabetes MellitusNutrientObesityPathologyPathway interactionsPhosphorylationPhosphorylation SitePhosphotransferasesPlayProteinsRoleSerineSignal PathwaySignal TransductionTSC1 geneTSC1/2 geneTSC2 geneTailTuberous sclerosis protein complexTumor Suppressor ProteinsTyrosine PhosphorylationVeinsbaseeffective therapyendoplasmic reticulum stressfeedinghigh riskimprovedin vivoinsulin receptor serine kinaseinsulin receptor substrate 1 proteininsulin signalingmTOR proteinmouse modelnovel therapeutic interventionnovel therapeuticsprotein degradationrecombinaseresponsesensor
项目摘要
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。我们以前已经表明,增加内质网(ER)应激和未折叠蛋白反应(UPR)信号通路的激活在胰岛素抵抗和肥胖2型糖尿病的发展中起着核心作用。UPR信号传导主要通过肌醇需要酶-1(IRE 1)介导的c-Jun氨基末端激酶-1(JNK 1)的活化和随后IRS-1在丝氨酸307处的磷酸化导致胰岛素抵抗的发展。脑硬化症复合体1和2(TSC 1和2)基因都编码肿瘤抑制因子。TSC 1和TSC 2在复合物中相关联,使得任一基因的缺陷破坏该复合物的功能,并导致雷帕霉素(mTOR)复合物1(mTORC 1)的哺乳动物靶标的不受控制的和异常的激活。mTORC 1通路的过度活跃导致严重的胰岛素抵抗。这在缺乏TSC 1或TSC 2的细胞中最明显。胰岛素刺激的IRS 1和IRS 2活化在TSC 1-/-和TSC 2-/-细胞中被完全阻断,同时IRS蛋白降解增加。然而,对IRS活性阻断和降解增强的分子机制知之甚少。我们的初步数据表明,缺乏TSC 1或TSC 2,以及随之而来的mTORC 1通路的过度活跃导致ER应激并激活UPR。通过化学伴侣4-苯基丁酸(4-PBA)阻断ER应激,显著改善胰岛素信号传导并完全阻断IRS-1降解,表明UPR在TSC缺乏的胰岛素抵抗的发展中起重要作用。我们的建议是基于这些发现,目的是调查在体内的作用,JNK-1和IRS-1 ser 307磷酸化在发展中的胰岛素抵抗在TSC 1缺陷的肝脏。
肥胖是一个快速增长的问题,是世纪对人类健康最严重的威胁之一。肥胖是胰岛素抵抗发生的最高风险。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。
项目成果
期刊论文数量(0)
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Umut Ozcan的其他文献
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{{ truncateString('Umut Ozcan', 18)}}的其他基金
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 - 财政年份:2010
- 资助金额:
$ 33.8万 - 项目类别:
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:
8210936 - 财政年份:2008
- 资助金额:
$ 33.8万 - 项目类别:
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:
7751212 - 财政年份:2008
- 资助金额:
$ 33.8万 - 项目类别:
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