PROJECT SUMMARY Despite progress in human papillomavirus (HPV) vaccination uptake, about three million women are still diagnosed with precancerous cervical lesions each year in the US. Most spontaneously regress, but yearly follow up and invasive prophylactic care (e.g., endocervical curettage and cervical biopsy) is still required as it is not clear which may progress to cervical cancer. Since Black women have more persistent HPV infections and precancerous lesions, as well as a higher incidence of cervical cancer than white women, they are disproportionately impacted by these invasive prophylactic procedures and their sequelae (e.g., pain, bleeding, scarring, infertility, future miscarriages, and preterm births). The vaginal microbiome (VMB) has been implicated in sustaining HPV infection and development of precancerous lesions. HPV-positive women, women with precancerous lesions, and Black women are more likely to have a suboptimal VMB with high taxonomic diversity with depletion of Lactobacillus spp. (both features of vaginal inflammation and dysbiosis) and are also associated with worse prognosis for precancerous lesions. My preliminary data shows that an optimal, Lactobacillus predominant VMB is protective against the risk of a precancerous cervical lesion for white but not Black women. Since the VMB is susceptible to the host micro and macro environments, it is plausible that these differences override the protective effect of the VMB in Black women. At the micro level, differences in species-specific metabolic profiles might be contributing to lesion prognosis by disturbing vaginal homeostasis. At the macro level, psychological stress, which is disproportionately experienced by Black women may be influencing the VMB through a cortisol pathway which has been biologically implicated with VMB dynamics and known to be dysregulated in Black women in response to stress. In this K01 application, I will test the hypothesis that racial differences in daily experiences of stress and respective cortisol response result in VMB changes that influence differential precancerous lesion regression by race. I will measure VMB changes and psychological (ecological momentary assessments), and physiological stress (salivary cortisol) among 75 Black and 75 White women diagnosed with a cervical lesion, assessed during the critical time between their routine pap screen and abnormal follow-up. The proposed mentorship, training and research will give me critical skills in bioinformatics, statistical and molecular biology to interrogate plausible mechanisms through which the VMB might underlie racially differential etiologies for pre-cancerous cervical lesions. The training described in this proposal will prepare me to become an independent translational investigator leading to the identification of practical solutions to the reduction of cancer outcome disparities.

PROJECT NARRATIVE This career development award proposes a multi-omic systems biology approach to elucidate the roles of the vaginal microbiome and psychological stress in progression of precancerous cervical lesions to cancer, notably, in the known disparities between Black and White women. The proposed plan will accelerate this early-stage investigator’s career trajectory to independence by providing targeted bioinformatic, statistical and molecular biology training to analyze microbiome and stress experience data, using an integrative systems biology framework to inform future clinically relevant prognostic biomarkers, risk stratification protocols, and interventions to intercept cervical cancer development.