Project 3-Cameron

项目3-卡梅伦

• 批准号: 10664038
• 负责人: Jennifer Erin Cameron
• 金额: $ 12.46万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10664038
• 关键词: Anal canal; Anogenital cancer; Antibodies; Anus; Biological; Biopsy; Carcinogens; Cell Compartmentation; Cell Cycle Regulation; Cells; Cervical; Cytology; DNA; DNA Damage; Data; Detection; Development; Dysplasia; EBV-encoded nuclear antigen 1; Epithelium; Epstein-Barr Virus Infections; Epstein-Barr virus encoded RNA 1; Etiology; Event; Foundations; Freezing; Gene Expression; Genetic Transcription; Genome; Genomics; HIV; HIV-1; HPV-High Risk; Human Herpesvirus 4; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Imaging Techniques; Immune response; Immunohistochemistry; In Situ Hybridization; Infection; Intervention; Knowledge; Lytic; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Mediating; Methods; Microdissection; Modeling; Modernization; Molecular; Mucous Membrane; Nature; Neoplasms; Oncogenes; Oncogenic; Oncogenic Viruses; Oncology; Oncoproteins; Pap smear; Pathway interactions; Persons; Predisposition; Prevalence; Proteins; Reporting; Research; Retinoblastoma Protein; Risk; Sentinel; TP53 gene; Testing; Tissues; Transcript; Uterine Cancer; Viral; Viral Genes; Viral Genome; Virus; Virus Diseases; Virus Integration; Visualization; Woman; Work; cancer risk; carcinogenesis; carcinogenicity; co-infection; cofactor; cohort; design; differential expression; effective intervention; in vivo; latency associated transcript; men; metaplastic cell transformation; molecular imaging; novel; premalignant; prevent; programs; repaired; response; spatial relationship; therapy design; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumorigenesis; viral DNA

PROJECT SUMMARY / ABSTRACT Oncogenic human papillomavirus (high risk HPV, or hrHPV) is the etiologic agent responsible for more than 90% of cancers of the uterine cervix and the anal canal (anogenital cancers). People living with human immunodeficiency virus (HIV) infection (PLWH) are particularly susceptible to hrHPV mediated anogenital cancers. People infected with high-risk HPV are at increased risk for cancer if the viral genome integrates into the host genome. The mechanisms by which hrHPV integration promotes tumorigenesis have been well described; however, the factors that promote hrHPV integration are largely unknown. The long-term objective of the proposed research is to identify these factors and then design effective interventions to prevent PLWH from developing anogenital cancers. Research has shown that PLWH who have anogenital high-risk HPV infection concurrently with another tumor virus, Epstein-Barr virus (EBV), are 3-6 times more likely to have pre-cancerous dysplasia than people who have anogenital hrHPV in the absence of EBV. This proposal investigates the hypothesis that EBV promotes integration of hrHPV genomes into the host genome by causing DNA damage. The general experimental approach will utilize cervical and anal tissues collected from hrHPV infected women and men to gain a better understanding of the interactions between hrHPV and EBV in anogenital tissue. The spatial relationship between hrHPV and EBV in co-infected tissue is a key determinant of the nature of the mechanistic interactions between the viruses; however, studies to date have failed to identify the cell compartment occupied by EBV in anogenital tissue. Therefore, the first Specific Aim of this proposal is to determine if hrHPV and EBV interact directly by co-infecting the same cell, or if they interact indirectly by infecting proximal but separate cell compartments, using cutting-edge in situ hybridization and immunohisto- chemistry approaches. The second Specific Aim is to begin to elucidate the effects of hrHPV-EBV co- infection on host and virus gene expression networks. Transcript expression in hrHPV-EBV co-infected anogenital tissue will be compared to that of hrHPV infected tissue using high-depth transcriptomics methods. Differential expression of host transcripts will reveal cellular pathways perturbed by hrHPV- EBV co-infection, including the effects of co-infection on DNA damage/repair pathways. Viral gene expression will be observed to determine a) if EBV is expressing latency transcripts associated with DNA damage and oncogenesis; b) if hrHPV is more likely to be integrated in the presence of EBV; and c) if EBV induces the expression of hrHPV oncogenes. Together these aims will inform the working model describing the mechanistic interactions between hrHPV and EBV in the context of anogenital cancer development, which will be further explored in a subsequent R01 proposal. These studies will illuminate opportunities for novel intervention strategies to prevent anogenital cancers in PLWH.

项目概要/摘要 致癌性人乳头瘤病毒（高危 HPV 或 hrHPV）是导致更多疾病的病原体。 超过 90% 的宫颈癌和肛管癌（肛门生殖器癌）。与人同住的人 人类免疫缺陷病毒 (HIV) 感染 (PLWH) 特别容易受到 hrHPV 介导的影响 肛门生殖器癌症。如果病毒基因组发生变化，感染高危 HPV 的人患癌症的风险就会增加 整合到宿主基因组中。 hrHPV整合促进肿瘤发生的机制 已得到很好的描述；然而，促进 hrHPV 整合的因素在很大程度上尚不清楚。这 拟议研究的长期目标是确定这些因素，然后设计有效的 预防艾滋病毒感染者患上肛门生殖器癌症的干预措施。研究表明，艾滋病病毒感染者 肛门生殖器高危 HPV 同时感染另一种肿瘤病毒 Epstein-Barr 病毒的人 (EBV)，患癌前发育不良的可能性比患有肛门生殖器发育不良的人高 3-6 倍 没有 EBV 的情况下的 hrHPV。该提案研究了 EBV 促进整合的假设 通过造成 DNA 损伤，将 hrHPV 基因组转移到宿主基因组中。一般实验方法 将利用从感染 hrHPV 的女性和男性身上收集的宫颈和肛门组织来获得更好的结果 了解肛门生殖器组织中 hrHPV 和 EBV 之间的相互作用。空间关系 共同感染组织中 hrHPV 和 EBV 之间的差异是机制性质的关键决定因素 病毒之间的相互作用；然而，迄今为止的研究未能确定细胞区室 被EBV占据在肛门生殖器组织中。因此，该提案的第一个具体目标是确定是否 hrHPV 和 EBV 通过共感染同一细胞直接相互作用，或者通过感染间接相互作用 使用尖端的原位杂交和免疫组织化学技术，近端但独立的细胞区室 化学方法。第二个具体目标是开始阐明 hrHPV-EBV 共同作用的影响 宿主和病毒基因表达网络的感染。 hrHPV-EBV 共感染的转录本表达 将使用高深度转录组学将肛门生殖器组织与 hrHPV 感染的组织进行比较 方法。宿主转录本的差异表达将揭示受 hrHPV-干扰的细胞通路 EBV 合并感染，包括合并感染对 DNA 损伤/修复途径的影响。病毒基因 将观察表达以确定 a) EBV 是否表达与 DNA 相关的潜伏转录物 损伤和肿瘤发生； b) hrHPV 是否更有可能在 EBV 存在的情况下整合； c) 如果 EBV 诱导 hrHPV 癌基因的表达。这些目标共同将为工作模式提供信息 描述肛门生殖器癌症背景下 hrHPV 和 EBV 之间的机制相互作用 开发，这将在后续的 R01 提案中进一步探讨。这些研究将阐明 预防艾滋病患者肛门生殖器癌症的新干预策略的机会。