Role of SH2-B in glucose metabolism
SH2-B 在葡萄糖代谢中的作用
基本信息
- 批准号:7332230
- 负责人:
- 金额:$ 27.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-02-15 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:AllelesAmino AcidsAnimalsBindingBinding ProteinsBirthCardiovascular DiseasesCellsCultured CellsDefectDrug Delivery SystemsEventFigs - dietaryFunctional disorderGenesGenetic TranscriptionGoalsHepaticHormonesIRS1 geneIRS2 geneInsulinInsulin ReceptorInsulin ResistanceInsulin Signaling PathwayInterventionJAK2 geneKnockout MiceLeadLeptinLinkLiverMeasuresMediatingMetabolic DiseasesMethodsMolecularMusMutant Strains MiceMutationNon-Insulin-Dependent Diabetes MellitusNumbersOrganPTPN1 genePathway interactionsPatientsPeripheralPhenotypePhosphorylationPhosphotransferasesPhysiologicalPlayProtein DephosphorylationProtein Tyrosine KinaseProtein Tyrosine PhosphataseProteinsReceptor ActivationReceptor Protein-Tyrosine KinasesRecombinantsRegulationResearchResistanceResponse ElementsRoleSH2B geneSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinSomatotropinTestingTissuesTyrosineTyrosine Phosphorylationanimal tissueblood glucose regulationcytokinediabeticdriving forceglucose metabolismhuman APS proteinhuman IRS2 proteinimprovedin vivoinhibitor/antagonistinsightinsulin receptor substrate 1 proteininsulin sensitivityinsulin signalingprogramspromoterreceptorreceptor bindingreconstitutionresponsesrc Homology Region 2 Domaintissue/cell culture
项目摘要
DESCRIPTION (provided by applicant): Insulin is the primary hormone regulating glucose homeostasis. It binds to and activates the insulin receptor (IR), which subsequently tyrosine phosphorylates and activates multiple cell signaling proteins including IRS proteins, APS and SH2-B. Defects in activation of IR and/or its downstream signaling molecules result in insulin resistance, which is associated with and may be a driving force for type 2 diabetes. The long-term goal of my research program is to elucidate the molecular mechanisms of insulin signaling and resistance. We recently identified SH2-B as a binding protein for IR as well as for JAK2, a cytosolic tyrosine kinase required for cytokine action. SH2-B binds to JAK2 via its SH2 domain, and enhances JAK2 kinase activity; however, its role in insulin action is unclear. To study the physiological function of SH2-B in vivo, we generated mutant mice lacking SH2-B. Initial inspection revealed that the mutant mice homozygous for the SH2-B null allele develop insulin resistance and type 2 diabetes. Moreover, hepatic IRS2 is reduced significantly in SH2-B deficient mice. We hypothesize that SH2-B enhances IR activation and IRS2 expression independently, and that both contribute to maintaining normal insulin sensitivity in animals. To test this hypothesis, we shall determine whether deletion of SH2-B impairs insulin-stimulated IR activation and the subsequent phosphorylation of its substrates and activation of downstream pathways, and whether reintroduction of recombinant SH2-B can rescues normal insulin signaling and physiological responses in SH2-B deficient cells and tissues. We shall determine whether SH2-B activates IRS2 promoter independent of insulin stimulation. We shall use a variety of methods to identify molecular mechanisms by which SH2-B potentiates IR activation and promotes IRS2 expression. Thus, the Specific Aims of this proposal are to:
1. Determine whether SH2-B directly enhances insulin physiological responses and signal transduction in mice, tissues and cultured cells.
2. Determine whether and how SH2-B enhances IR activation in mice, tissues and cultured cells.
3. Determine whether and how SH2-B enhances the IRS2 expression in mice, tissues and cultured cells.
The results of this proposal will lead to identification of SH2-B-initiated signaling events that may serve as targets for drug intervention of insulin resistance and type 2 diabetes.
描述(申请人提供):胰岛素是调节葡萄糖稳态的主要激素。它结合并激活胰岛素受体(IR),随后酪氨酸磷酸化并激活多种细胞信号蛋白,包括IRS蛋白、APS蛋白和SH2-B。IR和/或其下游信号分子激活缺陷导致胰岛素抵抗,这与2型糖尿病相关,并可能是其驱动因素。我的研究计划的长期目标是阐明胰岛素信号和抵抗的分子机制。我们最近发现SH2-B是IR和JAK2的结合蛋白,JAK2是细胞因子作用所需的胞质酪氨酸激酶。SH2- b通过其SH2结构域与JAK2结合,增强JAK2激酶活性;然而,它在胰岛素作用中的作用尚不清楚。为了研究SH2-B在体内的生理功能,我们培育了缺乏SH2-B的突变小鼠。初步检测显示,SH2-B零等位基因纯合的突变小鼠出现胰岛素抵抗和2型糖尿病。此外,在SH2-B缺陷小鼠中,肝脏IRS2显著降低。我们假设SH2-B独立地增强IR激活和IRS2表达,并且两者都有助于维持动物正常的胰岛素敏感性。为了验证这一假设,我们将确定SH2-B的缺失是否会损害胰岛素刺激的IR激活及其随后的底物磷酸化和下游通路的激活,以及重新引入重组SH2-B是否可以恢复SH2-B缺陷细胞和组织中正常的胰岛素信号传导和生理反应。我们将确定SH2-B是否独立于胰岛素刺激激活IRS2启动子。我们将使用多种方法来确定SH2-B增强IR激活和促进IRS2表达的分子机制。因此,本建议的具体目标是:
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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LIANGYOU RUI其他文献
LIANGYOU RUI的其他文献
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