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.

按种族和民族对脂质、抗氧化剂和渗透保护代谢物在更年期泌尿生殖综合征中的作用进行多组学和综合纵向评估。

• 批准号: 10643444
• 负责人: Joanna-Lynn C Borgogna
• 金额: $ 13.8万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643444
• 关键词: Advocate; Affect; Age; Aging; Alzheimer' s Disease; Anti-Inflammatory Agents; Antioxidants; Attenuated; Award; Biological Assay; Biological Markers; Cardiovascular Diseases; Cerebrospinal Fluid; Chronic; Chronology; Clinical; Clinical Data; Communities; Complex; Data; Development; Diagnosis; Diagnostic; Diet; Disease; Disparate; Doctor of Philosophy; Dryness; Elderly; Epidemiology; Epithelial Cells; Estrogen Therapy; Estrogens; Ethnic Origin; Evaluation; Exposure to; First Generation College Students; Genitourinary system; Glean; Glutathione; Glycine; Goals; Gynecologic; Health Care Costs; Human; Immunology; In Vitro; Inflammation; Inflammatory Response; Intervention; K-Series Research Career Programs; Knowledge; Latina; Link; Lipid Peroxidation; Lipids; Longitudinal cohort; Lubricants; Lubrication; Machine Learning; Mediating; Mediation; Medical; Menopausal Status; Menopausal Syndrome; Mentors; Metabolism; Metabolite Interaction; Methods; Microbe; Microbiology; Minority Women; Modality; Modernization; Mucous Membrane; Not Hispanic or Latino; Osmosis; Osteoporosis; Outcome; Oxidative Stress; Oxidative Stress Induction; Pain; Participant; Pathology; Phase; Plasma; Population; Postmenopause; Predisposition; Preparation; Prevention; Process; Pruritus; Publications; Quality of life; Race; Recurrence; Reproductive Biology; Research; Research Personnel; Risk; Role; Sampling; Serum; Sex Functioning; Sexual Health; Sexually Transmitted Diseases; Signs and Symptoms; Sphingolipids; Stress; Structural Models; Symptoms; Therapeutic Agents; Vagina; Validation; Vitamins; Woman; Work; Youth; age related; aged; antioxidant therapy; career; cell injury; cohort; cost; cytokine; early experience; estrogen disruption; ethnic minority; high risk; improved; infection rate; innovation; insight; lipid metabolism; machine learning method; marginalization; metabolome; metabolomics; microbial host; microbiome; microbiota; multiple omics; novel; novel therapeutics; older women; personalized intervention; post-doctoral training; racial minority; reduce symptoms; reproductive; side effect; skills; social stigma; statistics; vaginal lactobacilli; vaginal microbiota; validation studies

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.

绝经期泌尿生殖系统综合征是一种与年龄相关的慢性进行性泌尿生殖系统疾病 这对绝经后妇女的影响不成比例，每年为美国医疗保健贡献超过30亿美元 成本GSM的影响是广泛的，影响到超过6200万美国妇女。种族和少数民族是 不成比例地受到影响，但在老龄化和性健康相关研究中仍然代表性不足。阴道 微生物群是泌尿生殖和性健康的关键决定因素，我们假设这种关系可能是 通过宿主-微生物代谢物相互作用介导。随着女性年龄的增长，雌激素水平下降， 雌激素依赖过程。在一个大型队列（n=1190）中，我观察到实足年龄与 改变的脂质代谢（例如，脂质过氧化），保护性阴道乳酸杆菌的丧失，细胞损伤（例如， 增加的氧化应激代谢物），和阴道抗氧化剂的下降（例如，维生素）。氧化应激 诱导炎症，血清和血浆中氧化应激的生物标志物与年龄有关， 相关的病理（例如，骨质疏松症、心血管疾病和阿尔茨海默病）。一些抗氧化剂 可以由宿主产生（例如，谷胱甘肽），而其他必须通过饮食和微生物群获得 (e.g.,维生素）。抗氧化剂起到中和氧化和渗透压的作用， 对氧化应激相关病理的易感性。这还没有在阴道内描述过。K99 阶段提出（1）表征阴道LAO轮廓与生殖阶段、时间顺序 年龄和种族/民族;和（2）通过结合 机器学习、结构模型和多组学（代谢组学、免疫学和微生物群） 通过NIA奖励（R 01 AG 069915，PI：Shardell，共同申办者）可获得本提案所用的样本 并代表一个纵向队列（N=500名参与者; 25%种族/少数民族; 1200份样本）， GSM的症状和体征这将是最大的阴道代谢组学队列，强调绝经后 女人，至今。样本已经被送往微生物组，代谢组学和细胞因子分析。我会 完成免疫学，机器学习和结构模型的正式课程和指导， 为独立R 00阶段做准备，我建议在该阶段确定 在暴露于LAO代谢物和微生物群后的人阴道上皮细胞[HVEC]中。 在这项工作中收集的信息将有助于制定有针对性的干预措施（例如，抗氧化治疗） 并将告知R 01申请进行大规模、多中心验证研究， 管理GSM。所有的目标都将有助于我成为一名独立调查员的长期目标， 微生物学，重点是改善妇科结果和倡导可及性（降低成本， 个性化的干预目标），为历史上服务不足和边缘化的社区。 我的遗产将指导本提案的重点，并与MOSAIC K99/R 00目标保持一致。