Methods to Test Lifestyle, Vaginal Microenvironment, and Genitourinary Symptoms across Menopause Transition

测试更年期过渡期间生活方式、阴道微环境和泌尿生殖系统症状的方法

• 批准号: 10229293
• 负责人: REBECCA M. BROTMAN
• 金额: $ 79.57万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229293
• 关键词: 16S ribosomal RNA sequencing; Affect; Age; Aging; Alcohol consumption; Anaerobic Bacteria; Anti-Inflammatory Agents; Archives; Atrophic; Bacteria; Behavioral; Biochemical; Biogenic Amines; Biological; Biological Aging; Biological Markers; Biometry; Body mass index; Cells; Cervical; Clinical; Code; Complex; Computer software; Data; Data Analytics; Development; Dryness; Epidemiology; Epithelial; Epithelium; Estrogen Therapy; Estrogens; Funding; Genitourinary System Infection; Genitourinary system; Genomics; Glycogen; Goals; Growth Factor; Gynecology; Health; Human Papillomavirus; Immune; Immunologic Markers; Immunology; Immunology procedure; Inflammaging; Intervention; Kynurenine; Lactic acid; Lactobacillus; Lead; Life Style; Link; Longitudinal Studies; Lubricants; Machine Learning; Measures; Mediating; Mediation; Menopausal Symptom; Menopausal Syndrome; Menopause; Mental Depression; Methods; Microbiology; Mission; Modeling; Modernization; Molecular; Molecular Target; Multiomic Data; National Institute on Aging; Outcome; Perimenopause; Play; Postmenopause; Prevotella; Probiotics; Property; Public Health; Quality of life; Recording of previous events; Reporting; Risk; Role; Sampling; Sex Behavior; Sex Functioning; Sexual Dysfunction; Smoking; Source; Specimen; Statistical Methods; Streptococcus; Stress; Structural Models; Structure; Surveys; Swab; Symptoms; System; Systems Biology; Taurine; Testing; Thinness; Time; United States National Institutes of Health; Vagina; Visit; Woman; age related; aged; analytical method; base; cervicovaginal; chemokine; cohort; cytokine; dietary supplements; epidemiologic data; healthspan; high dimensionality; hormonal contraception; hormone therapy; improved; infection risk; innovation; lifestyle factors; microbial; microbiome; microbiome research; microbiota; microbiota metabolites; multidisciplinary; novel; novel strategies; novel therapeutics; pathogen; preservation; repository; side effect; statistics; urogenital tract; vaginal dryness; vaginal lactobacilli; vaginal microbiota; vaginal mucosa

Over 50% of postmenopausal women are affected by the genitourinary syndrome of menopause (GSM), which includes vaginal atrophy, vaginal dryness, and sexual dysfunction. Symptoms worsen if untreated and are associated with stress and depression. Estrogen decline in menopause is thought to lead to reduced glycogen accumulation in the vaginal epithelium and is associated with low vaginal Lactobacillus spp. levels in 50-80% of women. Lactobacillus spp. protect the urogenital tract from pathogens in part by producing lactic acid and for their anti-inflammatory properties, but whether lactobacilli are a marker for estrogen levels or play a functional role in GSM is unknown. Available treatments for vulvovaginal GSM symptoms have limitations. Some women are contraindicated for hormonal therapy or are concerned with side effects. Vaginal lubricants provide some relief, but they may be toxic to the vaginal epithelium, reduce lactobacilli, and raise urogenital infection risk. New therapies are needed. Vaginal microbiota are a plausible approach to treatment, however, probiotics alone have not proven effective. Vaginal microbiota co-vary with metabolite and immune profiles, and it is unknown how these molecular features relate to GSM. We hypothesize that core vaginal microenvironment biomarkers (VMB; e.g., microbial, metabolite, and immune profiles) reflect vaginal biological aging (V-BA) that is increased by menopause but may also be modifiable by other factors, such as lifestyle. Longitudinal studies are needed to identify core age-related VMB and determine how they relate to GSM. To accomplish this task, we will develop new statistical methods to combine complex longitudinal epidemiologic data with high- dimensional compositional data. We will leverage 2,301 archived cervicovaginal samples collected as part of a cohort of 812 women aged 35-60 years with visits every six months for two years (R01-CA123467). Specific Aims are to 1) quantify V-BA using VMB; 2) evaluate the longitudinal relationship between V-BA and GSM; 3) longitudinally assess the relationship of lifestyle factors on V-BA and VMB; 4) quantify longitudinal mediation by V-BA and VMB between lifestyle and GSM. Microbiota are already profiled by 16S rRNA gene amplicon sequencing (R21-AI107224). Along with clinical, demographic, and behavioral surveys, we will 1) use cervical secretions and multiplexed bead-based immune-assays to quantify concentrations of 70 immune markers (cytokines, chemokines, growth factors); 2) profile metabolites from vaginal swabs (GC/LC-MS). This proposal is focused on developing and validating new statistical methods that refine and adapt modern structural modeling and microbiota compositional analyses. The novel statistical approaches will allow identification of vaginal microenvironment features which may lead to development of new and effective GSM treatments. These methods will also provide a new framework to handle missing data and confounding that has limited prior microbiome studies. Our team has the multidisciplinary expertise in biostatistics, epidemiology, aging, gynecology, genomics, microbiology, and immunology required for a new systems-biology approach to GSM.

超过 50% 的绝经后女性受到更年期泌尿生殖综合症 (GSM) 的影响， 包括阴道萎缩、阴道干燥和性功能障碍。如果不治疗，症状会恶化 与压力和抑郁有关。更年期雌激素下降被认为会导致糖原减少 阴道上皮中的积累，与阴道乳酸杆菌属低水平有关。水平在 50-80% 的妇女。乳杆菌属部分通过产生乳酸来保护泌尿生殖道免受病原体侵害 它们的抗炎特性，但乳酸菌是否是雌激素水平的标志物或发挥功能性作用 在 GSM 中的作用尚不清楚。外阴阴道 GSM 症状的可用治疗方法有局限性。一些女性 禁忌激素治疗或担心副作用。阴道润滑剂提供一些 缓解，但它们可能对阴道上皮有毒，减少乳酸杆菌，并增加泌尿生殖感染的风险。 需要新的疗法。阴道微生物群是一种看似合理的治疗方法，但是益生菌 单独使用尚未被证明有效。阴道微生物群与代谢物和免疫特征共同变化，并且 尚不清楚这些分子特征与 GSM 有何关系。我们假设核心阴道微环境 生物标志物（VMB；例如微生物、代谢物和免疫特征）反映阴道生物老化 (V-BA)， 因更年期而增加，但也可能因其他因素（例如生活方式）而改变。纵向研究 需要识别与年龄相关的核心 VMB 并确定它们与 GSM 的关系。为了完成这个任务， 我们将开发新的统计方法，将复杂的纵向流行病学数据与高 维成分数据。我们将利用收集的 2,301 个存档的宫颈阴道样本，作为 812 名年龄在 35-60 岁的女性组成的队列，每六个月进行一次随访，持续两年 (R01-CA123467)。具体的 目标是 1) 使用 VMB 量化 V-BA； 2）评估V-BA与GSM之间的纵向关系； 3） 纵向评估生活方式因素对V-BA和VMB的关系； 4）量化纵向中介 通过 V-BA 和 VMB 在生活方式和 GSM 之间建立联系。 16S rRNA 基因扩增子已对微生物群进行了分析 测序（R21-AI107224）。除了临床、人口统计和行为调查外，我们将 1) 使用宫颈 分泌物和基于微珠的多重免疫测定可量化 70 种免疫标记物的浓度 （细胞因子、趋化因子、生长因子）； 2) 分析阴道拭子的代谢物 (GC/LC-MS)。这个提议 专注于开发和验证新的统计方法，以完善和适应现代结构 建模和微生物群组成分析。新的统计方法将允许识别 阴道微环境特征可能会导致新的有效 GSM 治疗方法的开发。 这些方法还将提供一个新的框架来处理缺失数据和混淆，这些数据有限 先前的微生物组研究。我们的团队拥有生物统计学、流行病学、老龄化、 GSM 的新系统生物学方法所需的妇科、基因组学、微生物学和免疫学。