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

基本信息

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
项目类别：
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

项目摘要

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.

宫颈癌差异的微生物组和粘膜免疫力居住在美国的非洲裔美国妇女继续承受着不当的负担宫颈癌，死亡率是欧美女性的2倍。这种生存差异在考虑社会经济状况和疾病阶段的考虑之后持续存在。高风险人的存在乳头瘤病毒（HPV）是宫颈癌和上皮内肿瘤的主要原因。预防性疫苗可用于最大的致癌类型，并且非常有效，但差异持续存在，并且接受疫苗的人数仍然是最佳的，特别是对于非裔美国妇女，对于已经感染了生殖器HPV的40％的美国女性人群中，疫苗无效。治疗选择对于高级阶段，转移性癌症是有限的。因此，新的治疗方法是需要，但是导致非裔美国妇女疾病发病机理的粘膜机制不是理解。因此，确定修改HPV持续性与的粘膜过程和/或介体清除和进展与宫颈肿瘤的减轻可能导致新的或改进的治疗方法，并且女性的CC结果更好。在此提案中，我们将调查女性微生物组和粘膜免疫的贡献非洲裔美国妇女宫颈癌健康差异的生殖道。这是基于相当大的来自我们实验室的数据和其他表明非洲裔美国妇女的阴道微生物比例更高营养不良；阴道微生物营养不良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有关的代谢产物；那个不植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美妇女相比，美国妇女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，包括宏基因组学，荟萃蛋白质组学，代谢组学，单细胞RNA测序和流式细胞仪研究阴道粘膜生物学在对非裔美国妇女的前瞻性研究中，再加上PV相关的宫颈的功能研究癌症小鼠模型，以更好地了解这些关系。