HPV: Biology, Clinical Significance and Epidemiology

HPV：生物学、临床意义和流行病学

• 批准号: 7673696
• 负责人: DENISE A. GALLOWAY
• 金额: $ 241.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673696
• 关键词: HPV; Biology; Clinical; Significance; Epidemiology

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，并确定仅导致部分HPV感染者进展为癌症的其他危险因素。以前，我们已经集中在一组高风险的属α hpv，并已表明他们有一个因果作用在肛门生殖器癌。此外，我们还发现了影响宫颈癌发展的免疫遗传因素。我们还发现了一些已知的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性器官癌中很常见。这促使我们将注意力转向另一种hpv病毒的可能性，即β - hpv属或EV hpv，与免疫抑制和紫外线有关