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.

更年期（GSM）的泌尿生殖综合征是与年龄相关的慢性泌尿生殖疾病 这不成比例地影响绝经后妇女，每年为美国医疗保健贡献30亿美元 费用。 GSM的影响是广泛的，影响了6200万美国妇女。种族和少数民族是 不成比例的影响，但在衰老和性健康相关研究中仍然不足。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。随着女性的年龄，雌激素水平下降破坏 雌激素依赖性过程。在大型队列中（n = 1190），我观察到时间顺序与 脂质代谢改变（例如脂质过氧化），受保护的阴道乳酸杆菌的丧失，细胞损伤（例如， 氧化应激代谢产物的增加），阴道抗氧化剂（例如维生素）的下降。氧化应激 诱导炎症，血清和血浆内氧化应激的生物标志物与年龄有关 相关病理（例如骨质疏松症，心血管疾病和阿尔茨海默氏病）。一些抗氧化剂 可以由宿主（例如，谷胱甘肽）产生，而其他则必须通过饮食和微生物群获得 （例如，维生素）。抗氧化剂可中和氧化物和渗透应激，其下降增加 对氧化应激相关病理的敏感性。在阴道中尚未描述这一点。 K99 （1）的相位提示表征了阴道老挝轮廓与生殖阶段的关系 年龄和种族/种族； （2）通过组合来量化老挝轮廓和GSM之间的纵向中介 机器学习，结构模型和多词（代谢组学，免疫学和微生物群）阴道 该提案的样品可通过NIA奖（R01AG069915，PI：Shardell，共同赞助商）获得。 并代表一个纵向队列（n = 500名参与者；种族/族裔少数族裔25％； 1200个样本） GSM的体征和症状。这将是最大的阴道代谢组人群，强调绝经后 迄今为止的女人。样品已经被发送用于微生物组，代谢组和细胞因子分析。我会 在免疫学，机器学习和结构模型中完成正式的课程和心理工作 准备独立R00阶段的准备，我建议确定的炎症反应 暴露于老挝代谢产物和微生物群后，人类阴道上皮细胞[HVEC]。 在这项工作期间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） 对于GSM，将为R01申请提供大规模的多中心验证研究，该申请将允许有针对性 GSM的管理。所有目标都将有助于我成为独立调查员的长期目标 微生物学的重点是改善妇科结果并提倡可及性（较低的成本， 为历史上服务不足和边缘化的社区的个性化目标）。 我的遗产将指导该提案的重点，并与马赛克K99/R00目标保持一致。