HPV: Biology, Clinical Significance and Epidemiology

HPV:生物学、临床意义和流行病学

基本信息

项目摘要

DESCRIPTION (provided by applicant): Our long-standing goal is to understand the role that human papillomaviruses (HPVs) play in the etiology of cancer, and to identify other risk factors that cause only some HPV infected individuals to progress to cancer. Previously we have focused on a group of high-risk genus alpha HPVs and have showed that they have a causal role in anogenital cancers. In addition, we identified immunogenetic factors that influenced the development of cervical cancer. We also identified a number of factors that were known or thought to be associated with immunosuppression, such as smoking and corticosteroid use that were common among the squamous cell anogenital cancers. This prompted us to direct our attention to the possibility that a different set of HPVs, known as genus beta- or EV HPVs, are involved (together with immunosuppression and UV damage) in the etiology of squamous cell cancer of the skin (SCSC). To test this hypothesis Project 1 will establish a nested case control study of SCSC among organ transplant recipients (OTR). We will identify the genus beta HPV types present in SCSC tumor tissue, the types and viral load resident in hair follicles of cases and controls, and HPV antibodies in blood samples drawn prior to transplantation. Associations with HPV markers will be estimated accounting for other SCSC risk factors such as immunosuppressive drugs, sunlight exposure and other characteristics. In a parallel longitudinal study, Project 1 will also examine the natural history of genus beta HPVs in the OTR population. Project 2 will focus on the mechanisms by which the genus beta E6 and E7 proteins contribute to malignancy by studying their ability to bypass UV damage checkpoints, inhibit apoptosis, disrupt p53 function and stimulate proliferation. We hypothesize that infection with genus beta HPVs can lead to increased proliferation of squamous cells, and that the HPV oncoproteins inhibit the normal response to UV-induced DNA damage, i.e. repair or apoptosis, allowing cells with mutations in tumor suppressors or oncogenes to accumulate changes that lead to cancer. Project 3 will focus on identifying genetic risk factors for HPV related cancers. For SCSC in OTRs, polymorphisms in genes in both the innate and adaptive immune response pathways will be interrogated, as well as genes in the UV-induced DNA damage repair pathway. We will also study polymorphisms in genes in the Toll-like receptor pathway in cervical and vulvar cancers, taking advantage of our large population-based cases and controls accrued in prior funding periods. Four cores will support these three projects: Molecular Biology, Pathology, Data Management and Biostatistics, and Administration. If a strong link between specific HPV types and SCSC can be verified in studies such as the ones we propose, this information will have important translational benefit in diagnosis, therapy and prevention. We bring an experienced, highly integrated, multidisciplinary team to address this important problem.
描述(由申请人提供):我们的长期目标是了解人乳头瘤病毒(HPV)在癌症病因学中的作用,并确定仅导致某些HPV感染个体进展为癌症的其他风险因素。以前,我们集中在一组高风险的α属HPV,并已表明它们在肛门生殖器癌中具有因果作用。此外,我们确定了影响宫颈癌发展的免疫遗传因素。我们还确定了一些已知或被认为与免疫抑制相关的因素,如吸烟和皮质类固醇的使用,这些因素在鳞状细胞肛门生殖器癌中很常见。这促使我们将注意力集中在一组不同的HPV,称为β-或EV HPV,参与的可能性上(与免疫抑制和UV一起)。 损伤)在皮肤鳞状细胞癌(SCSC)病因学中的作用。为了验证这一假设,项目1将在器官移植受者(OTR)中建立一项SCSC的巢式病例对照研究。我们将确定SCSC肿瘤组织中存在的β HPV类型,病例和对照毛囊中的类型和病毒载量,以及移植前抽取的血液样本中的HPV抗体。与HPV标志物的关联将估计其他SCSC风险因素,如免疫抑制药物,阳光照射和其他特征。在一项平行的纵向研究中,项目1还将检查OTR人群中β属HPV的自然史。项目2将重点研究β E6和E7蛋白通过研究其绕过紫外线损伤检查点、抑制细胞凋亡、破坏p53功能和刺激增殖的能力而导致恶性肿瘤的机制。我们假设β HPV感染可导致鳞状细胞增殖增加,HPV癌蛋白抑制对UV诱导的DNA损伤的正常反应,即修复或凋亡,使肿瘤抑制因子或癌基因突变的细胞积累导致癌症的变化。项目3将侧重于确定HPV相关癌症的遗传风险因素。对于OTR中的SCSC,将询问先天性和适应性免疫应答途径中的基因多态性,以及UV诱导的DNA损伤修复途径中的基因。我们还将研究宫颈癌和外阴癌中Toll样受体途径基因的多态性,利用我们在以前资助期间积累的大量基于人群的病例和对照。四个核心将支持这三个项目:分子生物学, 病理学、数据管理和生物统计学以及管理。如果特定HPV类型和SCSC之间的强有力联系可以在我们提出的研究中得到证实,那么这些信息将在诊断,治疗和预防方面具有重要的转化益处。我们拥有一支经验丰富、高度整合的多学科团队来解决这一重要问题。

项目成果

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DENISE A. GALLOWAY其他文献

DENISE A. GALLOWAY的其他文献

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{{ truncateString('DENISE A. GALLOWAY', 18)}}的其他基金

Human Papillomavirus and Polyomavirus Associated Malignancies.
人乳头瘤病毒和多瘤病毒相关恶性肿瘤。
  • 批准号:
    9762877
  • 财政年份:
    2017
  • 资助金额:
    $ 21.54万
  • 项目类别:
Human Papillomavirus and Polyomavirus Associated Malignancies.
人乳头瘤病毒和多瘤病毒相关恶性肿瘤。
  • 批准号:
    10601410
  • 财政年份:
    2017
  • 资助金额:
    $ 21.54万
  • 项目类别:
Human Papillomavirus and Polyomavirus Associated Malignancies.
人乳头瘤病毒和多瘤病毒相关恶性肿瘤。
  • 批准号:
    10219976
  • 财政年份:
    2017
  • 资助金额:
    $ 21.54万
  • 项目类别:
Human Papillomavirus and Polyomavirus Associated Malignancies.
人乳头瘤病毒和多瘤病毒相关恶性肿瘤。
  • 批准号:
    9389980
  • 财政年份:
    2017
  • 资助金额:
    $ 21.54万
  • 项目类别:
Human Papillomavirus and Polyomavirus Associated Malignancies.
人乳头瘤病毒和多瘤病毒相关恶性肿瘤。
  • 批准号:
    10461103
  • 财政年份:
    2017
  • 资助金额:
    $ 21.54万
  • 项目类别:
Human Papillomavirus and Polyomavirus Associated Malignancies.
人乳头瘤病毒和多瘤病毒相关恶性肿瘤。
  • 批准号:
    10669047
  • 财政年份:
    2017
  • 资助金额:
    $ 21.54万
  • 项目类别:
The Role of ALTO in the MCPyV Lifecycle and Tumorigenicity
ALTO 在 MCPyV 生命周期和致瘤性中的作用
  • 批准号:
    8653347
  • 财政年份:
    2014
  • 资助金额:
    $ 21.54万
  • 项目类别:
The Role of ALTO in the MCPyV Lifecycle and Tumorigenicity
ALTO 在 MCPyV 生命周期和致瘤性中的作用
  • 批准号:
    8797092
  • 财政年份:
    2014
  • 资助金额:
    $ 21.54万
  • 项目类别:
MOLECULAR BIOLOGY
分子生物学
  • 批准号:
    8307530
  • 财政年份:
    2011
  • 资助金额:
    $ 21.54万
  • 项目类别:
MOLECULAR MECHANISMS OF GENUS BETA E6 AND E7 PROTEINS
β E6 和 E7 属蛋白质的分子机制
  • 批准号:
    8307528
  • 财政年份:
    2011
  • 资助金额:
    $ 21.54万
  • 项目类别:

相似国自然基金

Journal of Integrative Plant Biology
  • 批准号:
    31024801
  • 批准年份:
    2010
  • 资助金额:
    24.0 万元
  • 项目类别:
    专项基金项目

相似海外基金

HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    7298629
  • 财政年份:
    1997
  • 资助金额:
    $ 21.54万
  • 项目类别:
HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    8118874
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    1997
  • 资助金额:
    $ 21.54万
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HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    7477983
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    1997
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    $ 21.54万
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HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    7883494
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    1997
  • 资助金额:
    $ 21.54万
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HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    7673696
  • 财政年份:
    1997
  • 资助金额:
    $ 21.54万
  • 项目类别:
HPV: BIOLOGY, CLINICAL SIGNIFICANCE AND EPIDEMIOLOGY
HPV:生物学、临床意义和流行病学
  • 批准号:
    3094025
  • 财政年份:
    1987
  • 资助金额:
    $ 21.54万
  • 项目类别:
HPV: BIOLOGY, CLINICAL SIGNIFICANCE AND EPIDEMIOLOGY
HPV:生物学、临床意义和流行病学
  • 批准号:
    3094017
  • 财政年份:
    1987
  • 资助金额:
    $ 21.54万
  • 项目类别:
HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    6512384
  • 财政年份:
    1987
  • 资助金额:
    $ 21.54万
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HPV: BIOLOGY, CLINICAL SIGNIFICANCE AND EPIDEMIOLOGY
HPV:生物学、临床意义和流行病学
  • 批准号:
    3094024
  • 财政年份:
    1987
  • 资助金额:
    $ 21.54万
  • 项目类别:
HPV: Biology, Clinical Significance and Epidemiology
HPV:生物学、临床意义和流行病学
  • 批准号:
    6881311
  • 财政年份:
    1987
  • 资助金额:
    $ 21.54万
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