A co-infection model for papillomavirus associated infections and cancers

乳头瘤病毒相关感染和癌症的共感染模型

• 批准号: 10667710
• 负责人: Nicole Marie Gilbert
• 金额: $ 24.88万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667710
• 关键词: Acceleration; Anti-Bacterial Agents; Atypia; Automobile Driving; Bacteria; Bacterial Vaginosis; Biochemical; Biological; Biological Assay; Biological Models; Cancer Etiology; Cervarix; Cervical dysplasia; Cervix Neoplasms; Cessation of life; Clinical Management; Contraceptive Agents; Contraceptive Usage; Cytology; DNA; Data; Development; Diagnostic; Disease Progression; Dysplasia; Epidemiology; Epithelial Cells; Epithelium; Estradiol; Evaluation; Female; Future; Gardasil; Gardnerella; Gardnerella vaginalis; Gonadal Steroid Hormones; Harvest; Histologic; Hormones; Human; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immune response; Impairment; Incidence; Infection; Inflammatory Response; Intervention; Irrigation; Kinetics; Lactobacillus; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Medroxyprogesterone; Medroxyprogesterone 17-Acetate; Modeling; Molecular; Monitor; Mucous body substance; Mus; Neoplasms; Observational Study; Organism; Pap smear; Papillomavirus; Papillomavirus Infections; Patients; Pre-Clinical Model; Predisposition; Prevotella; Process; Proteins; Publishing; RNA; Reporting; Ribosomal RNA; Risk; Role; Sampling; Sexually Transmitted Diseases; Squamous cell carcinoma; Testing; Time; Tissues; Vaccines; Vagina; Vaginal Human Papilloma Virus; Viral; Virus Diseases; Woman; Work; aged; cancer invasiveness; carcinogenesis; co-infection; cofactor; curative treatments; cytokine; genital infection; hormonal contraception; insight; intraepithelial; metagenomic sequencing; microbial; microbiome; microbiome components; mouse model; novel; novel diagnostics; novel therapeutic intervention; prophylactic; reproductive; reproductive tract; sex; therapy development; tool; translational study; tumor progression; vaginal microbiome; viral DNA

Abstract HPV infections are the most common sexually transmitted diseases and the primary cause of cervical cancer. Cervical cancer remains to be the fourth most common female malignancy and the second most common female cancer in women aged 15 to 44 years and is estimated to cause 91% of HPV-related cancer deaths. Every year approximately 5.5 million new HPV infections are reported in the U.S; Although 90% of infections can be cleared within two years, about 10% persistent HPV infections will ultimately progress to invasive cancers. The current prophylactic HPV vaccines (Gardasil and Cervarix) cannot clear established infections, which could take up to 25 years to progress to malignancy. Clinical management of HPV-related cancers is challenging because the robust early diagnostics and curative treatments are yet to be developed. HPV persistence is one key factor for cervical cancer. Accumulated evidence has demonstrated that women with high levels of bacterial vaginosis (BV)-associated anaerobic organisms are at increased risk of HPV persistence. However, the cause/effect of BV in cervical cancer remains elusive. Surprisingly little is known about the molecular processes underpinning the relationship between BV-associated bacteria and HPV because co-infection model systems have not been established. The interdisciplinary team of Dr. Gilbert for vaginal microbiome and Dr. Hu for papillomavirus will be most suitable to develop a co-infection model to study the dynamic roles of vaginal bacteria and papillomavirus persistence during cervical cancer development. Our overarching hypotheses guiding this proposal are that BV bacteria promote HPV persistence and tumor progression, and sex hormone contraceptives promote HPV persistence and cancer by disrupting the vaginal microbiome. More specifically, we will test these hypotheses in two specific aims of the current proposal: 1) BV bacteria promote HPV persistence and cancers by degrading the vaginal mucus barrier, disturbing the vaginal epithelium and/or by modulating host inflammatory responses to HPV infections (Aim 1). 2) Sex hormonal contraceptives promote HPV persistence and cancer in the genital tract by disrupting the vaginal microbiome (Aim 2). The rationales for these aims are based on previous published studies and current needs. Two common contraceptives depo medroxy-progesterone acetate (DMPA) and 17 beta-estradiol may impair colonization of lactobacilli and possibly compromise the vaginal barrier to viral infections leading to HPV persistence and cancer. We will develop a new co-infection mouse model system based on the expertise of two teams in two novel mouse models necessary to directly examine the basic premise of our hypotheses in two specific Aims. These studies will provide a starting place for more detailed microbiological and biochemical examinations of the mechanisms driving the BV-HPV association in cervical cancer. Findings of the current proposed study will have significant implications not only in providing novel insight to both the vaginal microbiome and papillomavirus fields but also in identifying interventions for future translational studies.

摘要 HPV感染是最常见的性传播疾病，也是宫颈癌的主要原因。 宫颈癌仍是女性第四大常见恶性肿瘤和第二大常见癌症 女性癌症发生在15岁至44岁的女性中，据估计占HPV相关癌症死亡的91%。 据报道，美国每年约有550万新的HPV感染；尽管90%的感染 可在两年内清除，约10%的持续性HPV感染最终将进展为侵袭性 癌症。目前的预防性HPV疫苗(Gardasil和Cervarx)无法清除已确定的感染， 这可能需要长达25年的时间才能进展为恶性肿瘤。HPV相关癌症的临床处理 具有挑战性，因为强有力的早期诊断和根治疗法尚未开发出来。人类乳头瘤病毒 坚持不懈是宫颈癌的关键因素之一。积累的证据表明，患有癌症的女性 与细菌性阴道病(BV)相关的高水平厌氧微生物感染HPV的风险增加 坚持不懈。然而，BV在宫颈癌中的因果关系仍然不清楚。令人惊讶的是，人们对此知之甚少 关于BV相关细菌与HPV之间关系的分子过程 因为共感染模型体系还没有建立起来。吉尔伯特博士的跨学科团队 阴道微生物组与胡博士针对乳头瘤病毒将最适合发展成混合感染模型进行研究。 阴道细菌和乳头瘤病毒在宫颈癌发生发展中的动态作用。我们的 指导这项提议的首要假设是，BV细菌促进HPV持续存在和肿瘤 进展，性激素避孕药通过破坏阴道促进HPV持久性和癌症 微生物组。更具体地说，我们将在当前提案的两个具体目标中测试这些假设：1)BV 细菌通过降解阴道粘液屏障，扰乱阴道，从而促进HPV持续存在和癌症 通过调节宿主对人乳头状瘤病毒感染的炎症反应(目标1)。2)性激素 避孕药通过破坏阴道微生物群促进HPV持续存在和生殖道癌症 (目标2)。这些目标的理论基础是基于之前发表的研究和当前的需求。二 常见避孕药中含有醋酸甲羟孕酮(DMPA)和17β-雌二醇可能会损害 乳酸菌的定植并可能损害导致HPV的病毒感染的阴道屏障 坚持不懈和癌症。我们将开发一种新的混合感染小鼠模型系统，该系统基于 两个团队在两个新的小鼠模型中需要直接检验我们在 有两个明确的目标。这些研究将为更详细的微生物学和生化研究提供一个起点 宫颈癌中BV-HPV相关性的机制检查。当前的调查结果 拟议的研究将具有重大意义，不仅在为阴道和阴道提供新的洞察力方面 不仅在微生物组和乳头瘤病毒领域，而且在为未来的翻译研究确定干预措施方面也是如此。