A multi-omic and integrative longitudinal evaluation of the role of lipid, antioxidant, and osmoprotectant metabolites in the genitourinary syndrome of menopause by race and ethnicity. - The genitourinary syndrome of menopause (GSM) is an age-related chronic, progressive urogenital condition that disproportionately affects postmenopausal women and contributes >$3 billion annually to US healthcare costs. The impact of GSM is extensive and affects >62 million US women. Racial and ethnic minorities are disproportionately affected but remain underrepresented in aging and sexual health related studies. The vaginal microbiota is a critical determinant in urogenital and sexual health, and we hypothesize this relationship may be mediated through host-microbial metabolite interactions. As women age, estrogen levels decline disrupting estrogen-dependent processes. In a large cohort (n=1190), I observed chronological aging to be associated with altered lipid metabolism (e.g., lipid peroxidation), loss of protective vaginal lactobacilli, cellular damage (e.g., increased oxidative stress metabolites), and a decline in vaginal antioxidants (e.g., vitamins). Oxidative stress induces inflammation, and biomarkers of oxidative stress within serum and plasma have been linked to age- related pathologies (e.g., osteoporosis, cardiovascular disease, and Alzheimer’s disease). Some antioxidants can be produced by the host (e.g., glutathione), while others must be obtained through the diet and microbiota (e.g., vitamins). Antioxidants serve to neutralize oxidative and osmotic stress and their decline increases susceptibility to oxidative stress related pathologies. This has not been yet described within the vagina. The K99 phase proposes to (1) Characterize the relation of vaginal LAO profiles with reproductive stage, chronological age, and race/ethnicity; and (2) Quantify the longitudinal mediation between LAO profiles and GSM by combining machine learning, structural models, and multi-omics (metabolomics, immunology, and microbiota) Vaginal samples leveraged for this proposal are available via an NIA award (R01AG069915, PI: Shardell, Co-Sponsor) and represent a longitudinal cohort (N=500 participants; 25% racial/ethnic minorities; 1200 samples) with varying signs and symptoms of GSM. This will be the largest vaginal metabolomic cohort emphasizing post-menopausal women, to date. Samples have already been sent for microbiome, metabolomic, and cytokine profiling. I will complete formal coursework and mentoring in immunology, machine learning, and structural models in preparation for the independent R00 phase where I propose to determine the inflammatory response of human vaginal epithelial cells [HVECs] following exposure to LAO metabolites and microbiota. Information gleaned during this work will be useful in developing targeted interventions (e.g., antioxidant therapy) for GSM and will inform an R01 application for a large-scale, multi-center validation study that will permit targeted management of GSM. All aims will contribute to my long-term goal of becoming an independent investigator in microbiology with a focus on improving gynecological outcomes and advocating accessibility (lower cost, personalized targets of intervention) for communities that have been historically underserved and marginalized. My heritage will direct the foci of this proposal and aligns with MOSAIC K99/R00 objectives.
