Regulation of nuclear transport in disease
疾病中核转运的调节
基本信息
- 批准号:8448628
- 负责人:
- 金额:$ 30.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:ArchitectureCell NucleusCell physiologyCellsChromatinCollectionComplexCytoplasmDNADataDefectDependenceDiseaseEnzymesFigs - dietaryGene ExpressionGene MutationGenesGenetic MaterialsGoalsGuanosine Triphosphate PhosphohydrolasesLaboratoriesLamin Type ALinkMembraneModelingMolecular TargetMutationNADPH OxidaseNuclearNuclear EnvelopeNuclear LaminaNucleotidesOrganellesOxidative StressPatientsPhenotypePlayPost-Translational Protein ProcessingPremature aging syndromeProductionProgeriaProteinsReactive Oxygen SpeciesReagentRegulationResearchRoleRunningSignal TransductionSiteSourceStressStructureStructure/Function NucleiSyndromeSystemTestingTissuesbasedisease phenotypedisease-causing mutationhuman diseaseinsightmouse modelmutantnucleocytoplasmic transportran GTP-Binding Proteinran-binding protein 1research studyscaffoldsensor
项目摘要
DESCRIPTION (provided by applicant): Mutations in structural components of the nuclear lamina cause a spectrum of human diseases known as laminopathies. Specific mechanisms for how disruption of the lamina generates cellular phenotypes have not been elucidated. This proposal tests a new hypothesis for how mutation of the gene encoding lamin A gives rise to cellular phenotypes in the premature aging disease, Hutchinson-Gilford Progeria Syndrome (HGPS). The proposal is based on data showing (i) the nucleocytoplasmic Ran gradient is disrupted in HGPS patient cells and this can be recapitulated in naive cells; (ii) Ran gradient disruption causes mis-localization of the SUMOylation enzyme Ubc9 from the nucleus to the cytoplasm; (iii) Reducing the levels of reactive oxygen species, which are elevated in HGPS cells, restores nuclear localization of the RanGTPase and Ubc9. The overall hypothesis is that constitutive anchoring of pre-lamin A to the nuclear membrane generates reactive oxygen species that inhibit the Ran GTPase System, disrupt the Ran gradient, relocalize Ubc9 to the cytoplasm, and induce cellular phenotypes in Progeria. Thus, defects in the nuclear lamina are transduced into cellular phenotypes, at least in part, via changes in the nuclear transport machinery. In Aim 1 we will determine the source and mechanism of reactive oxygen species induction by Progerin. In Aim 2 we test the hypothesis that the Ran GTPase System acts as a sensor for pre-lamin A- induced oxidative stress. In Aim 3 we test the hypothesis that the SUMO conjugating enzyme Ubc9 functions as an effector of oxidative stress by responding to the Ran gradient and modulating gene expression. Our studies bring a new perspective to the Progeria field, which includes a signaling and nuclear transport-based based framework to help understand how disease phenotypes are generated at the cellular level.
描述(由申请人提供):核层的结构成分中的突变会导致一种称为椎板病的人类疾病。尚未阐明椎板破坏如何产生细胞表型的特定机制。该提案检验了一个新的假设,即编码层粘连蛋白A的基因突变如何引起过早衰老疾病的细胞表型Hutchinson-Gilford Forperia综合征(HGPS)。该提案基于显示的数据(i)核细胞的RAN梯度在HGPS患者细胞中破坏,并且可以在幼稚的细胞中概括; (ii)运行梯度破坏会导致Sumoylation酶UBC9从细胞核到细胞质的错误定位; (iii)降低HGPS细胞中升高的活性氧的水平恢复了RANGTPase和UBC9的核定位。总体假设是,固定蛋白A向核膜的组成型锚定产生活性氧,从而抑制RAN GTPase系统,破坏RAN梯度,将UBC9重新定位到细胞质中,并在孕细胞中诱导细胞表型。因此,核层中的缺陷至少部分通过核转运机制的变化转化为细胞表型。在AIM 1中,我们将确定孕激素诱导活性氧的来源和机理。在AIM 2中,我们检验了RAN GTPase系统充当层固定蛋白A-诱导的氧化应激的传感器的假设。在AIM 3中,我们检验了共轭酶UBC9通过响应RAN梯度和调节基因表达的氧化应激的效应因子的假设。我们的研究为宫颈场带来了新的视角,其中包括一个基于信号和基于核能的信号传导和基于核转运的框架,以帮助了解如何在细胞水平上产生疾病表型。
项目成果
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Bryce Paschal其他文献
Bryce Paschal的其他文献
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