Role of a new polyomavirus in Merkel cell carcinoma

一种新的多瘤病毒在默克尔细胞癌中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): We have recently discovered a new human polyomavirus monoclonally-integrated into human Merkel cell carcinomas (MCC) that we call Merkel cell polyomavirus (MCPyV). MCC is a rare neuroectodermal cancer suspected to be caused by a viral infection because of its unusual epidemiology. It is the most aggressive skin cancer and only 50% of patients with advanced disease survive 9 months or longer. MCPyV has a 5.4 kbase genome closely related to murine and African green monkey lymphotropic polyomaviruses (MuPyV and LPyV, respectively). MCPyV is distantly related to SV40 and the four known human polyomaviruses. Human serosurveys show that 15-30% of populations from the US, Japan and Germany have cross-reactive antibodies to LPV which may actually represent reactivity to MCPyV infection. We find similar MCPyV infection rates using direct detection of MCPyV genome from peripheral blood cells. If confirmed, these findings suggest that over a billion persons have been exposed to MCPyV infections worldwide. Southern blotting shows that MCPyV is integrated into MCC genome at different sites in a somatic and monoclonal pattern. One cellular integration site has been defined as the receptor-type protein tyrosine phosphatase-gamma (PTPRG) intron 1. MCPyV also expresses a highly conserved T antigen in tumors. The N-terminus of MCPyV encodes transformation-associated DnaJ and LXCXE pocket protein-binding domains. All tumor- derived MCPyV T antigens, however, possess T antigen mutations that eliminate T antigen origin binding and/or plasmid replication functions. These functions are not needed to maintain integrated virus, suggesting that MCC arises in at least two steps: first, MCPyV integrates into the host genome; second, truncation mutations arise allowing expression of N-terminal transforming domains, but eliminating deleterious C- terminal domains. MCPyV may play a role in tumorigenesis through insertional mutagenesis, expression of T antigen or both. Our proposal seeks to understand these mechanisms for transformation and oncogenesis by 1) identifying additional cell integration sites, 2) analyzing T antigen transforming functions in rodent cells and in cell signaling assays, 3) performing cell-wide proteomic analysis following T antigen expression, 4) identifying novel cellular T antigen direct interactors and 5) generating transgenic mice with MCPyV T antigen expression targeted to Merkel mechanoreceptor cells. Through this systematic approach we anticipate we will learn how this new virus contributes to human carcinogenesis.
描述(由申请人提供):我们最近发现了一种新的人多瘤病毒,该病毒单克隆整合到人默克尔细胞癌(MCC)中,我们称之为默克尔细胞多瘤病毒(MCPyV)。MCC是一种罕见的神经外胚层癌,由于其不寻常的流行病学,怀疑是由病毒感染引起的。它是最具侵袭性的皮肤癌,只有50%的晚期患者存活9个月或更长时间。MCPyV具有5.4 kbase基因组,与鼠和非洲绿色猴嗜淋巴多瘤病毒(分别为MuPyV和LPyV)密切相关。MCPyV与SV 40和四种已知的人类多瘤病毒有远亲关系。人类血清调查显示,来自美国、日本和德国的15-30%的人群具有对LPV的交叉反应性抗体,其实际上可能代表对MCPyV感染的反应性。我们使用来自外周血细胞的MCPyV基因组的直接检测发现类似的MCPyV感染率。如果得到证实,这些研究结果表明,全球有超过10亿人暴露于MCPyV感染。Southern杂交结果表明,MCPyV以体细胞和单克隆的方式整合到MCC基因组的不同位点。一个细胞整合位点已被定义为受体型蛋白酪氨酸磷酸酶-γ(PTPRG)内含子1。MCPyV还在肿瘤中表达高度保守的T抗原。MCPyV的N-末端编码转化相关的DnaJ和LXCXE口袋蛋白结合结构域。然而,所有肿瘤来源的MCPyV T抗原都具有消除T抗原起点结合和/或质粒复制功能的T抗原突变。维持整合的病毒不需要这些功能,这表明MCC以至少两个步骤产生:首先,MCPyV整合到宿主基因组中;其次,出现截短突变,允许表达N-末端转化结构域,但消除有害的C-末端结构域。MCPyV可能通过插入突变、表达T抗原或两者在肿瘤发生中发挥作用。我们的建议试图通过以下方式来理解这些转化和肿瘤发生的机制:1)鉴定额外的细胞整合位点,2)分析啮齿动物细胞和细胞信号传导测定中的T抗原转化功能,3)在T抗原表达后进行细胞范围的蛋白质组学分析,4)鉴定新的细胞T抗原直接相互作用物和5)产生具有靶向默克尔机械感受器细胞的MCPyV T抗原表达的转基因小鼠。通过这种系统的方法,我们预计我们将了解这种新病毒如何有助于人类致癌。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

PATRICK S. MOORE其他文献

PATRICK S. MOORE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('PATRICK S. MOORE', 18)}}的其他基金

Discovery and Characterization of New Human Cancer Viruses
新人类癌症病毒的发现和表征
  • 批准号:
    10360576
  • 财政年份:
    2016
  • 资助金额:
    $ 39.74万
  • 项目类别:
Discovery and Characterization of New Human Cancer Viruses
新人类癌症病毒的发现和表征
  • 批准号:
    10115622
  • 财政年份:
    2016
  • 资助金额:
    $ 39.74万
  • 项目类别:
Role of a new polyomavirus in Merkel cell carcinoma
一种新的多瘤病毒在默克尔细胞癌中的作用
  • 批准号:
    8017493
  • 财政年份:
    2009
  • 资助金额:
    $ 39.74万
  • 项目类别:
Role of a new polyomavirus in Merkel cell carcinoma
一种新的多瘤病毒在默克尔细胞癌中的作用
  • 批准号:
    8215839
  • 财政年份:
    2009
  • 资助金额:
    $ 39.74万
  • 项目类别:
Role of a new polyomavirus in Merkel cell carcinoma
一种新的多瘤病毒在默克尔细胞癌中的作用
  • 批准号:
    7652877
  • 财政年份:
    2009
  • 资助金额:
    $ 39.74万
  • 项目类别:
Role of a New Polyomavirus in Merkel Cell Carcinoma
新型多瘤病毒在默克尔细胞癌中的作用
  • 批准号:
    8694310
  • 财政年份:
    2009
  • 资助金额:
    $ 39.74万
  • 项目类别:
MCC Tumor-Specific Biomarkers: Basis for Rational Therapy of Merkel Cell Carcinom
MCC 肿瘤特异性生物标志物:默克尔细胞癌合理治疗的基础
  • 批准号:
    8370549
  • 财政年份:
    2008
  • 资助金额:
    $ 39.74万
  • 项目类别:
MCC Tumor-Specific Biomarkers: Basis for Rational Therapy of Merkel Cell Carcinom
MCC 肿瘤特异性生物标志物:默克尔细胞癌合理治疗的基础
  • 批准号:
    8676455
  • 财政年份:
    2008
  • 资助金额:
    $ 39.74万
  • 项目类别:
Protein Biomarkers for a New Human Polyomavirus in AIDS-related Malignancies
艾滋病相关恶性肿瘤中新型人类多瘤病毒的蛋白质生物标志物
  • 批准号:
    7691836
  • 财政年份:
    2008
  • 资助金额:
    $ 39.74万
  • 项目类别:
MCC Tumor-Specific Biomarkers: Basis for Rational Therapy of Merkel Cell Carcinom
MCC 肿瘤特异性生物标志物:默克尔细胞癌合理治疗的基础
  • 批准号:
    8520225
  • 财政年份:
    2008
  • 资助金额:
    $ 39.74万
  • 项目类别:

相似海外基金

University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
  • 批准号:
    10073243
  • 财政年份:
    2024
  • 资助金额:
    $ 39.74万
  • 项目类别:
    Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
  • 批准号:
    10752129
  • 财政年份:
    2024
  • 资助金额:
    $ 39.74万
  • 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
  • 批准号:
    2339201
  • 财政年份:
    2024
  • 资助金额:
    $ 39.74万
  • 项目类别:
    Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
    MR/Y008693/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.74万
  • 项目类别:
    Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
  • 批准号:
    10076445
  • 财政年份:
    2023
  • 资助金额:
    $ 39.74万
  • 项目类别:
    Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
  • 批准号:
    23K14783
  • 财政年份:
    2023
  • 资助金额:
    $ 39.74万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
  • 批准号:
    23KJ0394
  • 财政年份:
    2023
  • 资助金额:
    $ 39.74万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
  • 批准号:
    10639161
  • 财政年份:
    2023
  • 资助金额:
    $ 39.74万
  • 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
  • 批准号:
    10752441
  • 财政年份:
    2023
  • 资助金额:
    $ 39.74万
  • 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
  • 批准号:
    10867639
  • 财政年份:
    2023
  • 资助金额:
    $ 39.74万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了