Cyclin requirements in gammaherpesvirus infection and disease
伽马疱疹病毒感染和疾病中的细胞周期素需求
基本信息
- 批准号:8329877
- 负责人:
- 金额:$ 30.63万
- 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:2012-07-01 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AnimalsBiochemicalBiochemistryBiological AssayBurkitt LymphomaBypassCDK6-associated protein p18Cancer BiologyCell CycleCell Cycle InhibitionCell ProliferationCellsChronicChronic DiseaseCyclin ACyclin ECyclinsDevelopmentDiseaseGenesGeneticGrantHerpesviridaeHodgkin DiseaseHomologous GeneHumanHuman Herpesvirus 4Human Herpesvirus 8ImmuneImmunocompetentImmunologic Deficiency SyndromesImmunosuppressionIn VitroIndividualInfectionInflammatoryIntegration Host FactorsInterventionInvestigationKaposi SarcomaKnowledgeLymphomaLymphoproliferative DisordersMalignant NeoplasmsMediatingModelingMolecularMusNasopharynx CarcinomaOutcomePathogenesisPathologyPathway interactionsPeritoneal FluidPhasePhosphotransferasesProcessPropertyRecombinantsReportingRisk FactorsRoleSatellite VirusesShapesSpecificityStagingTestingTherapeuticTransplantationTumor Suppressor ProteinsViralViral GenesVirusVirus DiseasesWorkcellular targetingcyclin D3gammaherpesvirusgene functiongenetic analysisin vivoin vivo Modelinhibitor/antagonistinsightkinase inhibitormouse modelpathogenprotein protein interactionreactivation from latencyrecombinant virustumorigenesisviral cyclin
项目摘要
DESCRIPTION (provided by applicant): Gammaherpesviruses result in lifelong infection associated with malignancies and other chronic disease in immune deficient individuals. The human gammaherpesviruses include Epstein Barr virus and Kaposi's Sarcoma associated virus, which are associated with Burkitt's lymphoma, Hodgkin's lymphoma, post-transplant lymphoproliferative disorder, nasopharyngeal carcinoma, peritoneal effusion lymphoma and Kaposi's sarcoma. Given the strict host specificity of the human gammaherpesviruses, a major challenge is to understand the host and viral factors that regulate the outcome of gammaherpesvirus infection in vivo, in both healthy and immune compromised individuals. This proposal makes extensive use of the mouse gammaherpesvirus 68, to investigate the genetic contribution of viral and host genes in shaping the outcome of infection. Through our previous work, we developed an extensive knowledge of the precise in vivo contexts in which a viral gene, the viral cyclin, promotes chronic infection. We identified seven different parameters of gammaherpesvirus infection and disease, including models of immune deficiency that are dependent on the virus encoded cyclin homolog. In this grant, we will dissect the molecular pathways used by the viral cyclin to promote infection in vivo, using recombinant viruses in which the viral cyclin has been replaced by alternate viral or cellular cyclins. We will characterize the viral cyclin activity in all cyclin dependent aspects of infection, identify the infected cell reservoir in presence and absence of the viral cyclin, and define the molecular mechanism of the viral cyclin in both persistent infection and reactivation from latency infection.
These recombinant viruses reveal distinct, non-overlapping mechanisms of viral cyclin action. Moreover, since different cellular cyclins are able to substitute for distinct phases of the viral infection, comparing the biochemical properties of different cyclins in distinct contexts of infection will result in significant insights in gammaherpesvirus infection and disease. By integrating our unique in vivo insights into the viral cyclin with these recombinant viruses and our identification of the cellular target of the viral cyclin in virus reactivation, this grant wil combine biochemistry and genetics, with in vitro and in vivo models of infection to define new molecular pathways that promote gammaherpesvirus infection and pathogenesis in the whole animal. Further, we propose to test candidate inhibitors of viral cyclins and viral cyclin dependent functions both in vitro and in vivo. Finally, our demonstration that host cyclins can facilitate virus infection and that a specific host tumor suppressor can repress virus reactivation
promises that our investigation of the virus encoded cyclins will advance the field of cancer biology beyond virus associated oncogenesis. These studies of the v-cyclin have, and will continue to yield fundamental insights into gammaherpesvirus infection and further elucidate new mechanisms by which gammaherpesvirus pathogenesis can be abrogated.
PUBLIC HEALTH RELEVANCE: The cellular cyclins have been strongly associated with tumorigenesis since their discovery, and while they were initially considered exclusively for regulating cell proliferation, recent studies show that frequent overlap in the cell proliferation functions, yet that their roles in cell fate, development and differentiation are distinct. Our studies of the virus encoded cyclins have identified that these cyclins are required at several stages of infection and pathogenesis, and that they work by at least two different mechanisms and that one of these mechanisms functions to oppose the activity of a cellular tumor suppressor protein. The work proposed here will define the mechanism of the viral cyclins during authentic infection and disease and will identify potential interventions relevant to human inflammatory disease and malignancies, both those associated with gammaherpesvirus infection and related to cellular cyclins and tumor suppressors.
描述(由申请人提供):伽马病毒导致免疫缺陷个体中与恶性肿瘤和其他慢性疾病有关的终生感染。人类γ瘤病毒包括爱泼斯坦巴尔病毒和卡波西的肉瘤相关病毒,这些病毒与伯基特的淋巴瘤,霍奇金的淋巴瘤,移植后淋巴细胞增生性疾病,鼻咽癌癌,全脊髓癌,全米内尼尔乳果lymphomamo and kaposi sarmaphoma和kaposi's sarmaposi有关。鉴于人类γ掌病毒的严格宿主特异性,一个主要的挑战是了解在健康和免疫受损的个体中,体内调节γHERPESVIRUS感染结果的宿主和病毒因素。该建议广泛使用小鼠γ掌病毒68,以研究病毒和宿主基因在塑造感染结果中的遗传贡献。通过我们以前的工作,我们对体内环境的精确知识有了广泛的了解,在体内环境中,病毒基因(病毒细胞周期蛋白)促进了慢性感染。我们确定了伽马梅病毒感染和疾病的七个不同参数,包括取决于病毒编码的细胞周期蛋白同源物的免疫缺陷模型。在这笔赠款中,我们将使用重组病毒被病毒细胞周期蛋白替换为替代病毒或细胞细胞周期蛋白代替的重组病毒,从而剖析病毒细胞周期蛋白用于促进感染的分子途径。我们将表征在感染的所有依赖性细胞周期依赖性方面的病毒细胞周期活性,在存在和不存在病毒细胞周期蛋白的情况下确定感染的细胞储存剂,并定义病毒细胞周期蛋白在持续性感染和潜伏感染中的反应激活中的分子机制。
这些重组病毒揭示了病毒细胞周期蛋白作用的不同,非重叠的机制。此外,由于不同的细胞细胞周期蛋白能够代替病毒感染的不同阶段,因此比较不同感染的不同环境中不同细胞周期蛋白的生化特性将导致对伽马梅病毒感染和疾病的重要见解。通过将我们独特的体内洞察力与这些重组病毒与病毒病毒的识别相结合到病毒细胞周期中在整个动物中促进γ掌病毒感染和发病机理的分子途径。此外,我们建议在体外和体内测试病毒细胞周期蛋白和病毒细胞周期蛋白依赖性功能的候选抑制剂。最后,我们证明宿主细胞周期蛋白可以促进病毒感染,并且特定的宿主抑制剂可以抑制病毒重新激活
承诺我们对病毒编码细胞周期蛋白的研究将使癌症生物学领域超越与病毒相关的肿瘤发生。这些对V-Cyclin的研究具有,并将继续对γ鞘病毒感染产生基本见解,并进一步阐明了可以消除γ鞘病毒发病机理的新机制。
公共卫生相关性:自发现以来,细胞细胞周期蛋白与肿瘤发生密切相关,虽然它们最初被视为仅用于调节细胞增殖,但最近的研究表明,细胞增殖功能的频繁重叠,但它们在细胞命运中的作用,但它们在发育中的作用,但区分是不同的。我们对病毒编码细胞周期蛋白的研究已经确定,这些细胞周期蛋白在感染和发病机理的几个阶段都需要,并且它们至少通过两种不同的机制起作用,并且其中一种机制起作用以反对细胞抑制蛋白的活性。这里提出的工作将定义真实感染和疾病期间病毒细胞周期蛋白的机制,并将确定与人类炎症性疾病和恶性肿瘤有关的潜在干预措施,包括与γ鞘病毒感染以及与细胞细胞周期蛋白和肿瘤抑制剂有关的干预措施。
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)
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Linda F. Van Dyk其他文献
Linda F. Van Dyk的其他文献
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{{ truncateString('Linda F. Van Dyk', 18)}}的其他基金
Non-coding RNAs in Gammaherpesvirus Infection and Disease
伽马疱疹病毒感染和疾病中的非编码 RNA
- 批准号:
9263885 - 财政年份:2016
- 资助金额:
$ 30.63万 - 项目类别:
Cyclin requirements in gammaherpesvirus infection and disease
伽马疱疹病毒感染和疾病中的细胞周期素需求
- 批准号:
8685199 - 财政年份:2012
- 资助金额:
$ 30.63万 - 项目类别:
Regulation of Herpesvirus Infection by Viral miRNAs
病毒 miRNA 对疱疹病毒感染的调控
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8535928 - 财政年份:2012
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$ 30.63万 - 项目类别:
Cyclin requirements in gammaherpesvirus infection and disease
伽马疱疹病毒感染和疾病中的细胞周期素需求
- 批准号:
8456067 - 财政年份:2012
- 资助金额:
$ 30.63万 - 项目类别:
Cyclin requirements in gammaherpesvirus infection and disease
伽马疱疹病毒感染和疾病中的细胞周期素需求
- 批准号:
8852568 - 财政年份:2012
- 资助金额:
$ 30.63万 - 项目类别:
Characterization of an animal model of chronic infection and disease
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$ 30.63万 - 项目类别:
Characterization of an animal model of chronic infection and disease
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- 资助金额:
$ 30.63万 - 项目类别:
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