Role of anal microbiota, local cytokines and HIV in persistence of high-risk human papillomavirus

肛门微生物群、局部细胞因子和 HIV 在高危人乳头瘤病毒持续存在中的作用

• 批准号: 9979821
• 负责人: Rebecca G. Nowak
• 金额: $ 13.54万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979821
• 关键词: Age; Anaerobic Bacteria; Anal canal; Anus; Archives; Bioinformatics; Biometry; Cell physiology; Cervical; Cervix Uteri; Characteristics; Coitus; Data; Detection; Ensure; Environment; Enzymes; Epithelial; Epithelium; Funding; General Population; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV risk; HIV therapy; HPV-High Risk; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immune Tolerance; Immunity; Immunology; Incidence; Individual; Infection; Institutes; Interdisciplinary Study; Intervention; Lead; Learning; Lesion; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of anus; Maryland; Mediating; Mentors; Mentorship; Modeling; Molecular Biology; Mucosal Immunity; Mucous Membrane; National Cancer Institute; Nigeria; Participant; Pathway interactions; Pattern; Population; Public Health; Recording of previous events; Research; Research Personnel; Research Proposals; Resources; Risk; Role; Sampling; Science; Squamous intraepithelial lesion; Swab; Time; Training; Uganda; Universities; Update; Uterine Lesion; Virus; Woman; Zimbabwe; anticancer research; antiretroviral therapy; cancer prevention; cancer risk; carcinogenesis; carcinogenicity; cohort; commensal bacteria; cytokine; experience; indexing; medical schools; men; men who have sex with men; microbial; microbiome; microbiome components; microbiota; multidisciplinary; preference; premalignant; prevent; programs; prospective; vaginal microbiome; virology

While uncommon in the general population, there is a marked (60-130 fold) increased risk of anal cancer in HIV-infected individuals, especially men who have sex with men (MSM). Anal cancer is caused by high-risk human papillomavirus (HR-HPV) that persists in the anal epithelium. It is currently not known whether HIV infection alters the anal micro environment, specifically the microbiota and cytokines, to increase persistence and eventually promote frank malignancy. The goals of the K07 are to undertake formal training and mentoring in microbiota, mucosal immunity, and molecular biology of carcinogenesis and to learn how to rigorously integrate these components analytically to identify cancer prevention markers. Therefore, our aims are to: 1) characterize the composition of the anal microbiota using hierarchical clustering and assess cluster membership with a persistently detected HR-HPV a year later for HIV- negative and HIV-positive men; 2) determine local cytokine profiles from anal swabs and assess their independent and mediating associations with persistent and non-persistent HR-HPV for those with and without HIV; and 3) describe the stability of cluster membership over time and whether that distinguishes persistence among HIV-negative and HIV-positive men. To achieve these aims, we propose to evaluate prospectively these mucosal interactions using archived anal swab samples from HIV-infected and HIV-uninfected MSM in an ongoing well characterized cohort, the TRUST/RV368 study in Nigeria (R01AI20913-01). Dr. Rebecca Nowak is an exceptional candidate whose research focuses on the mechanisms of HPV transformation during HIV infection. Much of her research has originated in Uganda, Zimbabwe, and Nigeria which has resulted in her focus on global cancer research, one of the priorities for the National Cancer Institute. Dr. Nowak has strong institutional support from the Institute of Human Virology at the University of Maryland School of Medicine. She will have guaranteed protected research time and access to a wealth of resources that will ensure a successful transition to an independently funded investigator. Her robust training plan includes: 1) high quality mentorship from her primary mentor, Dr. Kevin Cullen, as well as co-mentors in the field of microbiome (Dr. Jacque Ravel), biostatistics (Dr. Soren Bentzen), mucosal immunology (Dr. Raina Fichorova); 2) coursework in fundamental immunology with a focus on the mucosa; 3) training in bioinformatics; and 4) experience in multidisciplinary team science. With the training and experience, Dr. Nowak will be prepared to seek R01 funding to establish a multidisciplinary research program in carcinogenic viruses during HIV infection.

虽然在一般人群中并不常见，但其风险显著增加（60-130倍）。 艾滋病毒感染者的肛门癌，尤其是男男性行为者（MSM）。肛门 癌症是由高危型人乳头瘤病毒（HR-HPV）引起的，它在肛门中持续存在。 上皮目前尚不清楚艾滋病毒感染是否会改变肛门微环境， 特别是微生物群和细胞因子，以增加持久性，并最终促进弗兰克 恶性肿瘤K 07的目标是在微生物群方面进行正式的培训和指导， 粘膜免疫和致癌的分子生物学，并学习如何严格 分析整合这些成分以鉴定癌症预防标志物。所以我们的 目的是：1）使用层次聚类来表征肛门微生物群的组成 并评估一年后持续检测到HR-HPV的HIV的集群成员资格- 阴性和HIV阳性男性; 2）从肛门拭子中确定局部细胞因子谱，并评估 它们与持续性和非持续性HR-HPV的独立和中介关联， 那些有和没有艾滋病毒;和3）描述集群成员的稳定性随着时间的推移， 这是否区分了艾滋病毒阴性和阳性男性的持续性。实现 这些目标，我们建议前瞻性地评估这些粘膜的相互作用， 来自正在进行的井中的HIV感染者和未感染HIV的MSM的肛门拭子样本 特征队列，尼日利亚的TRUST/RV 368研究（R 01 AI 20913 -01）。丽贝卡医生 诺瓦克是一个特殊的候选人，他的研究重点是HPV的机制 艾滋病病毒感染期间的转化。她的大部分研究都起源于乌干达，津巴布韦， 和尼日利亚，这使她专注于全球癌症研究，这是 国家癌症研究所诺瓦克博士有强大的机构支持，从研究所 马里兰州医学院人类病毒学。她会保证 受保护的研究时间和获得丰富的资源，这将确保成功的 过渡到独立供资的调查员。她的强大的训练计划包括：1）高 来自她的主要导师Kevin Cullen博士以及该领域的共同导师的优质指导 微生物组学（Jacque Ravel博士），生物统计学（Soren Bentzen博士），粘膜免疫学（Dr. Raina Fichorova）; 2）基础免疫学课程，重点是粘膜; 3） 生物信息学培训; 4）多学科团队科学经验。与训练 和经验，诺瓦克博士将准备寻求R 01资金，建立一个多学科的 艾滋病毒感染过程中致癌病毒的研究计划。