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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.

微生物组和粘膜免疫在宫颈癌中的差异