Role of CMV kinase in regulating infection of ESC-derived neuroprogenitor cells
CMV 激酶在调节 ESC 来源的神经祖细胞感染中的作用
基本信息
- 批准号:8776910
- 负责人:
- 金额:$ 4.81万
- 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:2012-02-01 至 2016-01-31
- 项目状态:已结题
- 来源:
- 关键词:Antiviral AgentsApoptosisBiological ModelsBirthBrainCell CycleCell DeathCell Differentiation processCell LineCellsCessation of lifeChildChromatinCyclin-Dependent KinasesCytolysisCytomegalovirusCytomegalovirus InfectionsDataDeacetylaseDevelopmentDiploidyDisabled PersonsDiseaseEarly PromotersEffectivenessEmbryoEventExhibitsFellowshipFibroblastsFutureGene ExpressionGenomeGoalsHerpesviridaeHistonesHumanImmediate-Early GenesInfectionInfection preventionLifeLyticMediatingModelingMolecularMothersNervous System TraumaNeuraxisNeurogliaNeuronsNuclear Pore ComplexPathway interactionsPatternPharmacologic SubstancePhosphorylationPhosphotransferasesPost-Translational Protein ProcessingPregnancyProcessProtein KinaseProtein-Serine-Threonine KinasesProteomicsRecruitment ActivityRegulationRiskRoleSensorineural Hearing LossSpecificityTestingTimeToxic effectUnited StatesViralVirusVirus Diseasescell motilitycongenital cytomegaloviruscongenital infectiondevelopmental diseaseembryonic stem cellfetalhearing impairmenthistone modificationhuman HDAC1 proteininhibitor/antagonistkinase inhibitormaribavirneonatenerve stem cellneural precursor cellneuron developmentnon-geneticprecursor cellpreventprogenitorpromoter
项目摘要
DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) is the most common cause of non-hereditary sensorineural hearing loss in the U.S. Current therapies to treat infection during pregnancy or upon birth are unproven and risky. The experimental antiviral compound maribavir is a specific inhibitor of the CMV protein kinase, pUL97, and exhibits low toxicity. The objective of my proposal is to identify the molecular mechanism behind pUL97 kinase-mediated regulation of CMV gene expression and determine the impact of inhibiting kinase activity on CMV infected embryonic stem cell-derived neuronal progenitor cells. I have demonstrated that inhibition of the CMV kinase resulted in decreased expression of viral immediate early (IE) genes. This is a newly identified function of the CMV pUL97 kinase. Our lab previously identified an interaction between the CMV pUL97 kinase and cellular histone deacetylase 1 (HDAC1). HDAC1 acts as a repressor and is recruited to the MIE promoter at early times during infection. Therefore, I hypothesize that the kinase activity of CMV pUL97 influences the histone modification pattern at the viral major immediate early promoter by altering cellular HDAC1 activity. I propose to evaluate the pUL97-dependent changes of histone modifications at the major immediate early promoter (MIEP) during infection. These studies will be initiated using human diploid fibroblasts. In addition, I will identify pUL97-mediated changes in HDAC1 localization within the infected cells and at the MIEP. Other herpesvirus kinases phosphorylate HDAC1 and I propose several approaches to identify potential changes in HDAC1 phosphorylation by pUL97. I will determine the impact of these changes on HDAC1 deacetylase activity. I will further these studies using an embryonic stem cell-derived neural progenitor cell line (ES-NPCs) as a model system for CMV-induced neurological damage due to congenital CMV infection. Expression of IE genes has been demonstrated to alter fetal/neonate NPC differentiation. CMV IE genes regulate cell cycle and apoptosis in human diploid fibroblasts. I will test the role of pUL97 during these early events in the context of ES-NPC's by confirming the major results that were obtained in our fibroblast studies. I will determine the effectiveness of maribavir in preventing the pathogenic effects of HCMV infection on neuronal development. My studies will determine if a pUL97 kinase inhibitor is suitable for treating CMV infected neonates and possibly CMV infected mothers at risk of congenital infection.
描述(由申请人提供):人类巨细胞病毒(CMV)是美国当前在怀孕期间或出生后治疗感染的非遗传性感觉性听力损失的最常见原因。实验性抗病毒化合物Maribavir是CMV蛋白激酶PUL97的特异性抑制剂,并且表现出低毒性。我的建议的目的是确定PUL97激酶介导的CMV基因表达调节的分子机制,并确定抑制激酶活性对CMV感染的胚胎干细胞衍生的神经祖细胞的影响。我已经证明,对CMV激酶的抑制作用导致病毒直接早期(IE)基因的表达降低。这是CMV PUL97激酶的新鉴定功能。我们的实验室先前鉴定出CMV PUL97激酶与细胞组蛋白脱乙酰基酶1(HDAC1)之间的相互作用。 HDAC1充当阻遏物,并在感染期间早期招募给MIE启动子。因此,我假设CMV PUL97的激酶活性通过改变细胞HDAC1活性来影响病毒主要早期启动子的组蛋白修饰模式。我建议在感染过程中评估主要早期启动子(MIEP)在主要早期启动子(MIEP)上的PUL97依赖性变化。这些研究将使用人二倍体成纤维细胞开始。此外,我将确定受感染细胞和MIEP中HDAC1定位的PUL97介导的变化。其他疱疹病毒激酶磷酸化HDAC1,我提出了几种方法,以鉴定pul97磷酸化的潜在变化。我将确定这些变化对HDAC1脱乙酰基酶活性的影响。我将使用胚胎干细胞衍生的神经祖细胞系(ES-NPC)作为CMV诱导的神经系统损害的模型系统,进一步研究这些研究。 IE基因的表达已被证明可以改变胎儿/新生儿NPC分化。 CMV IE基因调节人二倍体成纤维细胞中的细胞周期和凋亡。我将通过确认在我们的成纤维细胞研究中获得的主要结果,在ES-NPC的早期事件中测试PUL97的作用。我将确定Maribavir在防止HCMV感染对神经元发育的致病作用方面的有效性。我的研究将确定PUL97激酶抑制剂是否适用于治疗感染CMV的新生儿以及可能感染先天性感染风险的CMV感染母亲。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Tarin M Bigley其他文献
Tarin M Bigley的其他文献
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{{ truncateString('Tarin M Bigley', 18)}}的其他基金
Establishing the impact of roseolovirues on development of autoimmunity due to loss of central tolerance
确定玫瑰病毒由于中枢耐受性丧失而对自身免疫发展的影响
- 批准号:
10591246 - 财政年份:2023
- 资助金额:
$ 4.81万 - 项目类别:
Role of CMV kinase in regulating infection of ESC-derived neuroprogenitor cells
CMV 激酶在调节 ESC 来源的神经祖细胞感染中的作用
- 批准号:
8256085 - 财政年份:2012
- 资助金额:
$ 4.81万 - 项目类别:
Role of CMV kinase in regulating infection of ESC-derived neuroprogenitor cells
CMV 激酶在调节 ESC 来源的神经祖细胞感染中的作用
- 批准号:
8601418 - 财政年份:2012
- 资助金额:
$ 4.81万 - 项目类别:
Role of CMV kinase in regulating infection of ESC-derived neuroprogenitor cells
CMV 激酶在调节 ESC 来源的神经祖细胞感染中的作用
- 批准号:
8421399 - 财政年份:2012
- 资助金额:
$ 4.81万 - 项目类别:
Role of CMV kinase in regulating infection of ESC-derived neuroprogenitor cells
CMV 激酶在调节 ESC 来源的神经祖细胞感染中的作用
- 批准号:
8990945 - 财政年份:2012
- 资助金额:
$ 4.81万 - 项目类别:
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