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.

宫颈癌患者微生物群和粘膜免疫功能的差异 生活在美国的非裔美国妇女继续承受着不必要的更高的负担 宫颈癌和a&gt；死亡率是欧美女性的2倍。这种生存差距 在考虑了社会经济地位和疾病阶段后仍坚持。高危人群的存在 人乳头瘤病毒(HPV)是宫颈癌和宫颈上皮内瘤变的主要病因。预防用药 针对最具致癌性的类型的疫苗是可用的，并且是高效的，但存在差异和 接种疫苗的人数仍然不理想，特别是对非裔美国女性来说，而且 疫苗对40%已经感染生殖器HPV的美国女性人口无效。治疗方案 因为晚期癌症是有限的，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的粘膜机制并不是 很好理解。因此，确定改变HPV持久性的粘膜突起和/或介体与 宫颈肿瘤的清除和进展与缓解可能导致新的或改进的治疗和 为女性提供更好的CC结果。 在这项建议中，我们将研究微生物群和粘膜免疫在雌性中的作用 非裔美国女性患宫颈癌的健康差异与生殖道有关。这是建立在相当大的基础上的 来自我们实验室和其他机构的数据显示，非裔美国女性的阴道微生物比例更高 微生物失调；阴道微生物失调与宫颈粘膜的促炎和癌症途径有关； 这些细菌产生的代谢物与免疫抑制表型有关； 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 与欧美女性相比，美国女性表现出更多的激活炎症途径。 在这个概念中，我们将利用最先进的系统生物学技术，包括元基因组学， 代谢组学、单细胞RNA测序和流式细胞术在阴道粘膜生物学研究中的应用 在对非裔美国女性的前瞻性研究中，加上与PV相关的宫颈功能研究 癌症小鼠模型，以更好地了解这些关系。