Approximately 11,000 new cases of cervical cancer were diagnosed in the US in 2018. While the cervical cancer mortality rate declined, approximately 4,000 women still die from this disease every year. According to Indian Health Service data from 1999-2009, Native American (NA) women had approximately a two-fold higher incidence and associated mortality rate than White women. Hispanic and NA women have the highest rates of cervical cancer in Arizona, with respectively, 7.8 and 7.1 cases per 100,000 women. While HPV is the known etiologic agent of cervical cancer, few studies were conducted to estimate HPV prevalence within NA communities. Among those studies, it was reported that 22.2% of NA women from the Hopi reservation in northeastern Arizona tested positive for HPV infection. The deficiencies of both cervical screening and higher HPV prevalence are likely contributors to cervical cancer disparities among NA women. Yet, evidence suggests an association of HPV infection, persistence, and disease progression with vaginal microbiota (VMB) features, which were reported to differ across socioeconomic or ethnic/racial groups. Despite differences in cervical cancer rates between racial and ethnic groups, little is known about the patterns of HPV infection and VMB composition in NA communities, or how these factors relate to increased cervical cancer risk. In fact, most prior studies do not include NA women. We hypothesize that there are dual factors (Indigenous perceptions and biological factors within the cervicovaginal microenvironment) that contribute to HPV persistence and, ultimately, cervical cancer health disparities in Native women. For this 3-year full project, we will continue working with the MedStar Health Research Institute in Phoenix, AZ. Thus, the aims of this project are to (1) assess the knowledge and perspectives of cultural practices, HPV-associated cancers, and STI knowledge among urban NA women, and (2) define changes in the vaginal microbiota and immunometabolic milieu in a longitudinal study of urban NA women to better understand the relationship between these factors and HPV infection, persistence, and clearance. From these aims, we will (1) determine the prevalence of modifiable risk factors and behaviors for HPV infection and HPV-related cancers among NA women; (2) assess knowledge and perceptions regarding HPV-related cancers among NA women; (3) determine the individual HPV status, levels of vaginal inflammatory mediators, metabolites and the VMB abundance in NA women across a longitudinal study; (4) evaluate the risk factors associated with prevalent HPV types and the VMB; and (5) conduct integrated multi-omics analysis in NA women focused on features of the local microenvironment associated with HPV status. Therefore, this 3-year full project will include culturally-informed community-based biomedical research and apply Two Eyed Seeing as a guiding principle with the long-term goal of reducing health disparities that impa...