The role of XMRV, a newly discovered human retrovirus, in cancer pathogenesis
XMRV(一种新发现的人类逆转录病毒)在癌症发病机制中的作用
基本信息
- 批准号:8629705
- 负责人:
- 金额:$ 29.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-09 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAntibodiesAntigensAutopsyBiological AssayBloodBlood CellsCell Culture TechniquesCell LineCellsClonalityComplementary DNADNADNA IntegrationDevelopmentDiseaseEpidemiologic StudiesExcisionFreezingGammaretrovirusGeneral PopulationGenesGenetic PolymorphismGenotypeGoalsHamstersHistocompatibility TestingHistologicHumanImmune SeraImmunohistochemistryIn VitroIndividualInfectionInflammationInsertional ActivationsLaboratoriesLeadLengthLife Cycle StagesLinkLongevityMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of prostateMapsMinkModalityMoloney Leukemia VirusMonoclonal AntibodiesMorbidity - disease rateMurine leukemia virusMutationNucleic AcidsOncogenicOperative Surgical ProceduresPC3 cell lineParaffin EmbeddingPathogenesisPlayPopulationPopulations at RiskPrevalencePrevalence StudyProcessProstateProstaticProtein BiosynthesisProteinsProvirusesRadical ProstatectomyRat virusRecombinant ProteinsReportingRetroviridaeReverse TranscriptionRibonucleasesRoleSamplingSan FranciscoSequence AnalysisSerumSiteSpecimenStagingTestingTimeTissuesTransfectionTropismVariantViralViral ProteinsVirionVirusVirus DiseasesVirus ReplicationWomancancer preventioncancer therapycarcinogenesiscell typeenv Gene Productsinfected vector rodentlifetime riskmRNA Expressionmalemenmortalitynovelnucleocytoplasmic transportparticleprognosticpublic health relevancereceptorrecombinant peptidetissue tropismtooltumortumorigenesisviral DNA
项目摘要
DESCRIPTION (provided by applicant): Prostate cancer is the most common form of non-skin cancer in US men (1). The lifetime risk for developing prostate cancer is approximately one in six in the US (2). Morbidity and mortality due to prostate cancer are likely to grow further given increasing longevity. Epidemiologic studies indicate that infection and inflammation may play a role in the development of prostate cancer (3, 4). A recent search for viral nucleic acids in prostate cancer tissues led to the identification of a novel retrovirus, Xenotropic murine leukemia virus-related virus (XMRV) in approximately 10% of prostate cancers tested (5). XMRV, by sequence analysis, is a gammaretrovirus. While gammaretroviruses have well- characterized oncogenic effects in animals, they have not been shown to cause human cancers. Our preliminary results show that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to another gammaretrovirus, Moloney murine leukemia virus (MoMLV). We analyzed 334 consecutive prostate resection specimens using a quantitative PCR assay and immunohistochemistry with an anti-XMRV specific antiserum. We found XMRV in 27% of prostate cancers and in only 6% of non-cancer controls, showing for the first time an association of XMRV with prostate cancer. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. The presence of XMRV correlated with higher-grades of prostate cancers. We found XMRV infection to be unrelated to a common polymorphism in the RNASEL gene, unlike previously reported. This increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant, to all individuals. Our goal is to further understand pathogenesis by XMRV, to determine if this virus causes prostate cancer, and delineate possible mechanisms for oncogenesis. We will also carry out epidemiological studies to study the prevalence and tropism of this new and important virus. Our specific aims are: Aim 1: Characterization of XMRV replication in cell culture; testing mechanisms of oncogenesis: We will use the full- length replication-competent DNA clone of XMRV that we have assembled, and the polyclonal XMRV-specific antisera we have generated to characterize different steps in the viral life cycle. Aim 2: Further characterization of XMRV infection in human prostate cancers. We will continue our analysis of large numbers of de-identified human prostate cancers. We will further characterize the presence and localization of XMRV within cancers of different grades, stages and histologic subtypes and its association with different prognostic features of prostate cancer. Aim 3: Epidemiological studies to look for prevalence of XMRV in the general population: in blood, and in tissues other than prostate. Our studies could causally link XMRV to carcinogenesis and lead to novel modalities for cancer prevention and treatment.
描述(由申请人提供):前列腺癌是美国男性最常见的非皮肤癌形式(1)。在美国,患前列腺癌的终生风险约为六分之一(2)。随着寿命的延长,前列腺癌的发病率和死亡率可能会进一步增长。流行病学研究表明,感染和炎症可能在前列腺癌的发展中发挥作用(3,4)。 最近对前列腺癌组织中病毒核酸的研究发现,在约10%的前列腺癌中发现了一种新型逆转录病毒,即异嗜性鼠白血病病毒相关病毒(XMRV)(5)。通过序列分析,XMRV是一种γ逆转录病毒。虽然γ逆转录病毒在动物中具有良好特征的致癌作用,但尚未显示它们引起人类癌症。我们的初步结果表明,XMRV确实是一种γ逆转录病毒,其蛋白质组成和颗粒超微结构与另一种γ逆转录病毒Moloney鼠白血病病毒(MoMLV)高度相似。我们分析了334个连续的前列腺切除标本使用定量PCR检测和免疫组化与抗XMRV特异性抗血清。我们在27%的前列腺癌中发现了XMRV,而在非癌症对照组中仅为6%,这首次表明XMRV与前列腺癌相关。XMRV蛋白主要在恶性上皮细胞中表达,表明逆转录病毒感染可能与肿瘤发生直接相关。XMRV的存在与较高级别的前列腺癌相关。我们发现XMRV感染与RNASEL基因中常见的多态性无关,不像以前报道的那样。这增加了XMRV感染风险的人群,从仅RNASEL变体纯合的人群增加到所有个体。 我们的目标是进一步了解XMRV的发病机制,以确定这种病毒是否会导致前列腺癌,并描绘肿瘤发生的可能机制。我们亦会进行流行病学研究,研究这种新的重要病毒的流行情况和嗜性。我们的具体目标是:目标1:细胞培养物中XMRV复制的表征;测试肿瘤发生的机制:我们将使用我们组装的XMRV的全长复制能力DNA克隆和我们产生的多克隆XMRV特异性抗血清来表征病毒生命周期中的不同步骤。目的2:进一步表征人前列腺癌中XMRV感染。我们将继续分析大量去识别的人类前列腺癌。我们将进一步描述XMRV在不同级别、阶段和组织学亚型的癌症中的存在和定位,以及其与前列腺癌不同预后特征的相关性。目的3:流行病学研究,以寻找XMRV在一般人群中的患病率:在血液和前列腺以外的组织中。我们的研究可能将XMRV与致癌作用联系起来,并导致癌症预防和治疗的新模式。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
T-Cell lymphoblastic lymphoma presenting as bilateral multinodular breast masses: a case report and review of the literature.
T 细胞淋巴母细胞淋巴瘤表现为双侧多结节性乳腺肿块:病例报告和文献综述。
- DOI:10.1002/ajh.20448
- 发表时间:2005
- 期刊:
- 影响因子:12.8
- 作者:Vakiani,Efsevia;Savage,DavidG;Pile-Spellman,Eliza;El-Tamer,Mahmoud;Singh,IlaR;Murty,VundavalliS;Alobeid,Bachir;Bhagat,Govind
- 通讯作者:Bhagat,Govind
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ILA R SINGH其他文献
ILA R SINGH的其他文献
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{{ truncateString('ILA R SINGH', 18)}}的其他基金
The role of XMRV, a newly discovered human retrovirus, in cancer pathogenesis
XMRV(一种新发现的人类逆转录病毒)在癌症发病机制中的作用
- 批准号:
8040941 - 财政年份:2010
- 资助金额:
$ 29.09万 - 项目类别:
The role of XMRV, a newly discovered human retrovirus, in cancer pathogenesis
XMRV(一种新发现的人类逆转录病毒)在癌症发病机制中的作用
- 批准号:
8211071 - 财政年份:2010
- 资助金额:
$ 29.09万 - 项目类别:
The role of XMRV, a newly discovered human retrovirus, in cancer pathogenesis
XMRV(一种新发现的人类逆转录病毒)在癌症发病机制中的作用
- 批准号:
8460966 - 财政年份:2010
- 资助金额:
$ 29.09万 - 项目类别:
New approach to study West Nile virus fusion into cells
研究西尼罗河病毒融入细胞的新方法
- 批准号:
7267936 - 财政年份:2006
- 资助金额:
$ 29.09万 - 项目类别:
New approach to study West Nile virus fusion into cells
研究西尼罗河病毒融入细胞的新方法
- 批准号:
7144925 - 财政年份:2006
- 资助金额:
$ 29.09万 - 项目类别:
A novel approach to study hepatitis C virus entry
研究丙型肝炎病毒进入的新方法
- 批准号:
6531660 - 财政年份:2002
- 资助金额:
$ 29.09万 - 项目类别:
A novel approach to study hepatitis C virus entry
研究丙型肝炎病毒进入的新方法
- 批准号:
6653801 - 财政年份:2002
- 资助金额:
$ 29.09万 - 项目类别:
HIGH RESOLUTION FUNCTIONAL MAPPING OF RETROVIRAL GENES
逆转录病毒基因的高分辨率功能图谱
- 批准号:
6169577 - 财政年份:1999
- 资助金额:
$ 29.09万 - 项目类别:
HIGH RESOLUTION FUNCTIONAL MAPPING OF RETROVIRAL GENES
逆转录病毒基因的高分辨率功能图谱
- 批准号:
6372657 - 财政年份:1999
- 资助金额:
$ 29.09万 - 项目类别:
HIGH RESOLUTION FUNCTIONAL MAPPING OF RETROVIRAL GENES
逆转录病毒基因的高分辨率功能图谱
- 批准号:
2885499 - 财政年份:1999
- 资助金额:
$ 29.09万 - 项目类别:
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