The Microbiome and Mucosal Immunity in Cervical Cancer Disparities

宫颈癌差异中的微生物组和粘膜免疫

• 批准号: 10347718
• 负责人: Stefanie Avril
• 金额: $ 55.95万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-25 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347718
• 关键词: Accounting; Address; Affect; African; African American; American; Anaerobic Bacteria; Arginine; Bacteria; Biological Markers; Biology; Butyrates; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervix Neoplasms; Cessation of life; Clinic; Cohort Studies; Colposcopy; Communities; Coupled; Data; Databases; Developing Countries; Disease; Disease Progression; Disease remission; Disseminated Malignant Neoplasm; Environment; Epithelial; European; FRAP1 gene; Female; Female genitalia; Flow Cytometry; Functional disorder; Gardnerella vaginalis; Gene Expression; Gene Proteins; Generations; Genital; Genitalia; HPV-High Risk; High Prevalence; Human Papillomavirus; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunology; Immunosuppression; In Vitro; Inflammation; Inflammatory; Infrastructure; Interleukin-6; Intervention; Lactobacillus; Lead; Limited Stage; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measurement; Mediator of activation protein; Metagenomics; Mobiluncus; Molecular; Molecular Profiling; Mucosal Immunity; Mucous Membrane; Mus; Outcome; Pathogenesis; Pathology; Pathway interactions; Persons; Phenotype; Population; Preventive vaccine; Prevotella; Process; Propionates; Prospective Studies; Regulatory T-Lymphocyte; Role; Sampling; Socioeconomic Status; Systems Biology; T-Lymphocyte; TNF gene; Techniques; The Cancer Genome Atlas; Time; Tissues; Treatment outcome; Tryptophan; Tryptophan 2,3 Dioxygenase; Uganda; United States; Vaccines; Vagina; Woman; base; cancer health disparity; cancer risk; carcinogenicity; cost effective; dysbiosis; experience; health disparity; high risk; improved; in vivo; metabolomics; metaproteomics; microbial; microbiome; microbiome research; microorganism; mortality; mouse model; novel therapeutic intervention; predictive marker; prospective; recruit; reproductive tract; single-cell RNA sequencing; survival disparity; tumor progression; tumor-immune system interactions; vaccine access; vaginal microbiome; vaginal mucosa

The microbiome and mucosal immunity in cervical cancer disparities African American women living in the United States continue to experience an undue higher burden of cervical cancer and a >2 times higher mortality rate than European American women. This survival disparity persists after accounting for socioeconomic status and disease stage. The presence of high-risk human papillomavirus (HPV) is the major cause of cervical cancer and cervical intraepithelial neoplasia. Prophylactic vaccines are available against the most carcinogenic types and are highly effective, but disparities persist and the number of people receiving the vaccine remains suboptimal especially for African American women, and the vaccine is ineffective for the 40% of female US population already infected with genital HPV. Treatment options for advanced stages are limited, and metastatic cancer is incurable. New therapeutic approaches are therefore needed but the mucosal mechanisms contributing to disease pathogenesis in African American women are not well understood. Therefore, identifying mucosal processes and/or mediators which modify HPV persistence vs clearance and progression vs remission of cervical neoplasia could lead to new or improved treatments and better CC outcomes for women. In this proposal we will investigate the contribution of the microbiome and mucosal immunity in the female genital tract to health disparities in cervical cancer in African American women. This is built upon considerable data from our lab and others that show that African American women have higher proportion of vaginal microbial dysbiosis; that vaginal microbial dysbiosis is linked to pro-inflammatory and cancer pathways in cervical mucosa; that these bacteria produce metabolites that are linked to an immunosuppressive phenotype; that dysbiotic bacteria can induce cancer pathways in vitro; and cervical cancer tissue gene expression data from African American women show increased activation inflammatory pathways compared to European American women. In this concept we will utilize state-of-the-art systems biology techniques, including metagenomics, metaproteomics, metabolomics, single cell RNA sequencing and flow cytometry to study vaginal mucosal biology in prospective studies of African American women, coupled with functional studies in PV-associated cervical cancer mouse models, to better understand these relationships.

宫颈癌差异中的微生物组和粘膜免疫 生活在美国的非裔美国妇女继续承受着不适当的更高负担 宫颈癌的死亡率比欧洲美国女性高 2 倍以上。这种生存差距 在考虑了社会经济状况和疾病阶段后仍然存在。高危人群的存在 乳头瘤病毒（HPV）是宫颈癌和宫颈上皮内瘤变的主要原因。预防性 疫苗可针对大多数致癌类型并且非常有效，但差异仍然存在， 接受疫苗的人数仍然不理想，特别是对于非裔美国妇女而言，而且 疫苗对 40% 已感染生殖器 HPV 的美国女性无效。治疗方案 对于晚期癌症的治疗效果有限，而且转移性癌症是无法治愈的。因此新的治疗方法 需要，但导致非裔美国女性疾病发病机制的粘膜机制尚不明确 很好理解。因此，识别改变 HPV 持久性的粘膜过程和/或介质 宫颈肿瘤的清除和进展与缓解可能会导致新的或改进的治疗方法 女性获得更好的 CC 效果。 在本提案中，我们将研究微生物组和粘膜免疫对女性的贡献 生殖道对非裔美国女性宫颈癌健康差异的影响。这是建立在相当大的 我们实验室和其他实验室的数据表明，非裔美国女性的阴道微生物比例较高 生态失调；阴道微生物失调与宫颈粘膜的促炎和癌症途径有关； 这些细菌产生与免疫抑制表型相关的代谢物；那个失调的 细菌可以在体外诱导癌症途径；以及来自非洲的宫颈癌组织基因表达数据 与欧洲美国女性相比，美国女性的炎症通路激活程度更高。 在这个概念中，我们将利用最先进的系统生物学技术，包括宏基因组学、 宏蛋白质组学、代谢组学、单细胞 RNA 测序和流式细胞术研究阴道粘膜生物学 对非裔美国女性的前瞻性研究，以及与 PV 相关的宫颈功能研究 癌症小鼠模型，以更好地理解这些关系。