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总宫颈癌发病率的80％。在博茨瓦纳，尚未仔细探索艾滋病毒阳性女性宫颈癌的发生率之间的联系。此外，通过最近的研究，包括与默克尔细胞多瘤病毒相关的默克尔细胞癌（包括默克尔细胞癌），传染病与癌症之间的联系增加了。这强调了这些药物的重要性及其对致癌过程的贡献。超过20％的人类癌症与传染剂有关，该估计可能低于实际数量。包括从组织和其他材料中恢复核酸的技术和方法的进步极大地提高了我们检测和确认相关癌症中这些药物鉴定的能力。项目＃1的拟议研究的总体目的是确定传染剂对博茨瓦纳HIV阳性女性宫颈癌发展的贡献。博茨瓦纳艾滋病毒阳性女性宫颈癌发病率的这种急剧增加，可以带来其他药物的潜在贡献以及炎症反应，这共同导致更快，更加增强的反应。我们的项目将利用我们在波斯特瓦纳（Bostwana）独特的3个女性，这使我们能够监视从HPV和HIV阴性妇女到HIV和HPV阳性的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展有关的其他药物（微生物签名）。我们的工作假设是，多种药物可以为博茨瓦纳艾滋病毒阳性女性宫颈癌的发展做出贡献，这可能导致炎症反应（炎症签名），从而协同导致宫颈癌。我们将利用我们新开发的组合策略，该策略将微阵列技术桥梁具有高吞吐量测序。这些药物的鉴定将在组织中验证这些药物在组织中的存在，感染细胞的转录分析以及与相关药物的先天和适应性炎症反应的分析，并使用原代宫颈上皮细胞的体外模型系统研究了对这些细胞的增殖作用。