Natural History & Pathogenesis of HPV in HIV infected women with cervical cancer

自然历史

• 批准号: 8936659
• 负责人: ERLE S. ROBERTSON
• 金额: $ 10.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8936659
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Antigens; Automobile Driving; Biological Assay; Biological Models; Botswana; Cancer Burden; Carcinoma; Cell Line; Cells; Cervical; Cervical dysplasia; Cervix Uteri; Cervix carcinoma; Communicable Diseases; Country; Cytokine Receptors; Development; Disease Progression; Epithelial Cells; Epithelium; Family; Freezing; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Gynecologist; HIV; HIV Seropositivity; HPV-High Risk; Health; High-Throughput Nucleotide Sequencing; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Immunohistochemistry; In Situ Hybridization; Incidence; Income; Individual; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Label; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Merkel Cells; Merkel cell carcinoma; Microarray Analysis; Molecular; Monitor; Natural History; Nucleic Acid Probes; Nucleic Acids; Oncogenic; Oncogenic Viruses; Operative Surgical Procedures; Pathogenesis; Pathologist; Patients; Pattern; Polyomavirus; Population; Precancerous Conditions; Process; Recovery; Recruitment Activity; Research; Risk; Role; Sampling; Sexually Transmitted Diseases; Signaling Protein; Technology; Tissue Sample; Tissues; Transcript; Universities; Vagina; Validation; Viral; Virus; Woman; Work; cohort; combinatorial; high risk; improved; in vitro Model; insight; microbial; next generation sequencing; pathogen; prevent; prospective; protein protein interaction; response; screening

The cervical cancer burden in low and middle income countries make up about 80% of the total cervical cancer incidence worldwide. In Botswana the link between increased incidences of cervical cancer in HIV positive women has not been carefully explored. Furthermore there is an increased link between infectious disease and cancer as seen by additional recent studies including the presence of Merkel Cell Carcinomas linked to the Merkel Cell Polyoma virus. This underscores the importance of these agents and their contributions to the oncogenic process. Greater than 20% of human cancers are associated with infectious agents and that estimate is likely to be lower than the actual number. The advances in technology and approaches which include recovery of nucleic acids from tissues and other materials has greatly improved our ability to detect and confirm the identifications of these agents in associated cancers. The overall goal of the proposed studies in project #1 is to determine the contributions of infectious agents to development of cervical carcinomas in HIV positive women in Botswana. This dramatic increase in cervical cancer incidence in HIV-positive women in Botswana allows for the potential contributions of additional agents as well as the inflammatory response which together leads to a more rapid and proliferative response. Our project will take advantage of our unique 3 cohorts of women in Bostwana that allows us to monitor changes in the cervical flora from HPV and HIV-negative women to women with cervical cancer who are HIV and HPV positive. Our initial question will be to identify additional agents (microbial signature) which may be linked to development of cervical carcinomas in this population. Our working hypothesis is that multiple agents can contribute to the development of cervical carcinomas in HIV-positive women in Botswana and this can result in an inflammatory response (inflammatory signature) which synergistically leads to cervical carcinomas. We will utilize our newly developed combinatorial strategy which bridges microarray technology with high throughput sequencing. The identification of these agents will be followed by validation of the presence of these agents in tissues, transcription analysis of infected cells as well as analysis of the innate and adaptive inflammatory responses with the associated agents, and investigating the proliferative effects on these cells using an in vitro model system of primary cervical epithelial cells.

低收入和中等收入国家的宫颈癌负担约占全球宫颈癌总发病率的80%。在博茨瓦纳，艾滋病毒阳性妇女宫颈癌发病率增加之间的联系尚未得到仔细探讨。此外，最近的其他研究表明，传染病和癌症之间的联系越来越紧密，包括与默克尔细胞多瘤病毒相关的默克尔细胞癌的存在。这强调了这些物质的重要性及其对致癌过程的贡献。超过 20% 的人类癌症与传染源有关，这一估计可能低于实际数字。技术和方法的进步，包括从组织和其他材料中回收核酸，极大地提高了我们检测和确认相关癌症中这些药物的能力。项目#1 中拟议研究的总体目标是确定传染源对博茨瓦纳艾滋病毒阳性妇女患宫颈癌的影响。博茨瓦纳艾滋病毒呈阳性的妇女宫颈癌发病率急剧增加，这可能是其他药物以及炎症反应的潜在贡献，这些因素共同导致了更快速和增殖性的反应。我们的项目将利用我们在博茨瓦纳独特的 3 组女性的优势，使我们能够监测从 HPV 和 HIV 阴性女性到 HIV 和 HPV 阳性宫颈癌女性的宫颈菌群变化。我们最初的问题是确定可能与该人群中宫颈癌的发生有关的其他物质（微生物特征）。我们的工作假设是，多种药物可能导致博茨瓦纳艾滋病毒阳性女性患宫颈癌，这可能导致炎症反应（炎症特征），从而协同导致宫颈癌。我们将利用我们新开发的组合策略，将微阵列技术与高通量测序结合起来。在鉴定这些物质之后，将验证这些物质在组织中的存在，对受感染细胞进行转录分析，以及对相关物质的先天性和适应性炎症反应进行分析，并使用原代宫颈上皮细胞体外模型系统。