Regulation of nuclear transport in disease

疾病中核转运的调节

• 批准号: 8664768
• 负责人: Bryce Paschal
• 金额: $ 32.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8664768
• 关键词: Architecture; Cell Nucleus; Cell physiology; Cells; Chromatin; Collection; Complex; Cytoplasm; DNA; Data; Defect; Dependence; Disease; Enzymes; Figs - dietary; Gene Expression; Gene Mutation; Genes; Genetic Materials; Goals; Guanosine Triphosphate Phosphohydrolases; Laboratories; Lamin Type A; Link; Membrane; Modeling; Molecular Target; Mutation; NADPH Oxidase; Nuclear; Nuclear Envelope; Nuclear Lamina; Nucleotides; Organelles; Oxidative Stress; Patients; Phenotype; Play; Post-Translational Protein Processing; Premature aging syndrome; Production; Progeria; Proteins; Reactive Oxygen Species; Reagent; Regulation; Research; Role; Running; Signal Transduction; Site; Source; Stress; Structure; Structure/Function Nuclei; Syndrome; System; Testing; Tissues; base; disease phenotype; disease-causing mutation; human disease; insight; mouse model; mutant; nucleocytoplasmic transport; ran GTP-Binding Protein; ran-binding protein 1; research study; scaffold; sensor

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）：核纤层结构成分的突变会导致一系列称为核纤层病的人类疾病。椎板破坏如何产生细胞表型的具体机制尚未阐明。该提案测试了一个新假设，即编码核纤层蛋白 A 的基因突变如何引起早衰疾病哈钦森-吉尔福德早衰综合症 (HGPS) 的细胞表型。该提议基于的数据显示：(i) HGPS 患者细胞中的核细胞质 Ran 梯度被破坏，这可以在初始细胞中重现； (ii) Ran梯度破坏导致SUMO化酶Ubc9从细胞核错误定位到细胞质； (iii) 降低 HGPS 细胞中升高的活性氧水平，恢复 RanGTPase 和 Ubc9 的核定位。总体假设是，核纤层蛋白前体 A 与核膜的组成性锚定会产生活性氧，从而抑制 Ran GTPase 系统，破坏 Ran 梯度，将 Ubc9 重新定位到细胞质，并诱导早衰症的细胞表型。因此，核纤层中的缺陷至少部分地通过核运输机制的变化转变成细胞表型。在目标 1 中，我们将确定 Progerin 诱导活性氧的来源和机制。在目标 2 中，我们测试了 Ran GTPase 系统作为前核纤层蛋白 A 诱导的氧化应激传感器的假设。在目标 3 中，我们测试了这样的假设：SUMO 结合酶 Ubc9 通过响应 Ran 梯度和调节基因表达而发挥氧化应激效应子的作用。我们的研究为早衰症领域带来了新的视角，其中包括基于信号传导和核运输的框架，以帮助了解疾病表型是如何在细胞水平上产生的。