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 生活在美国的非洲裔美国妇女继续承受着不应有的更高的生育负担。 宫颈癌和死亡率比欧洲美国妇女高2倍以上。这种生存差异 在考虑了社会经济地位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 针对大多数致癌类型的疫苗是可用的，并且非常有效，但差异仍然存在， 接种疫苗的人数仍然不理想，特别是对非洲裔美国妇女来说， 疫苗对已经感染生殖器HPV的40%的美国女性人口无效。治疗选择 对于晚期癌症的治疗是有限的，并且转移性癌症是不可治愈的。因此，新的治疗方法 需要，但导致非裔美国妇女疾病发病的粘膜机制并不存在 很好理解。因此，鉴定改变HPV持续性的粘膜过程和/或介质与 宫颈瘤变的清除和进展与缓解可能导致新的或改进的治疗， 更好地为女性提供CC结果。 在本提案中，我们将研究女性中微生物组和粘膜免疫的贡献。 非裔美国妇女宫颈癌中生殖道与健康的差异。这是建立在相当大的 来自我们实验室和其他实验室的数据显示，非裔美国妇女的阴道微生物比例较高， 生态失调;阴道微生物生态失调与宫颈粘膜中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代谢物; 细菌可以在体外诱导癌症途径;来自非洲的宫颈癌组织基因表达数据 与欧洲裔美国女性相比，美国女性显示出增加的激活炎症通路。 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， 元蛋白质组学、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 在非裔美国女性的前瞻性研究中，加上PV相关宫颈的功能研究 癌症小鼠模型，以更好地了解这些关系。

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.