Methods to Test the Role of Age-related Lifestyle and Vaginal Microenvironment Changes and the Prevention, Treatment, and Progression of Genitourinary Syndrome of Menopause

测试与年龄相关的生活方式和阴道微环境变化以及更年期泌尿生殖综合征的预防、治疗和进展的作用的方法

• 批准号: 10475571
• 负责人: REBECCA M. BROTMAN
• 金额: $ 64.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475571
• 关键词: 16S ribosomal RNA sequencing; Affect; Age; Aging; Alcohol consumption; Anaerobic Bacteria; Anti-Inflammatory Agents; Archives; Atrophic; Bacteria; Biochemical; Biogenic Amines; Biological; Biological Aging; Biological Markers; Biology of Aging; Biometry; Body mass index; Cells; Chronic; Chronic Disease; Clinical; Code; Collection; Complex; Computer software; Data; Data Analyses; Development; Epidemiology; Epithelial; Estrogen Therapy; Estrogens; Funding; Genitourinary System Infection; Genitourinary system; Genomics; Glycogen; Goals; Growth Factor; Gynecology; Human Papillomavirus; Immune; Immunologic Markers; Immunology; Inflammaging; Inflammation; Intervention; Kynurenine; Lactic acid; Lactobacillus; Lead; Life Style; Link; Lower urinary tract; Lubricants; Machine Learning; Measures; Mediating; Mediation; Menopausal Symptom; Menopausal Syndrome; Menopause; Metabolic; Methods; Microbiology; Modeling; Modernization; Molecular; Molecular Target; National Institute on Aging; Outcome; Perimenopause; Play; Postmenopause; Prevention; Prevotella; Probiotics; Production; Property; Prospective Studies; Public Health; Quality of life; Recording of previous events; Reporting; Risk; Role; Sampling; Sex Behavior; Sexual Dysfunction; Signs and Symptoms; Smoking; Statistical Methods; Streptococcus; Structural Models; Symptoms; System; Systems Biology; Taurine; Testing; Time; United States National Institutes of Health; Vagina; Visit; Vulva; Woman; Women' s Health; age related; aged; analytical method; biological specimen archives; cervicovaginal; chemokine; cohort; cost; cytokine; dietary supplements; dysbiosis; healthy aging; hormonal contraception; hormone therapy; infection risk; innovation; lifestyle factors; microbial; microbiome; microbiome composition; microbiome research; microbiota; microbiota metabolites; modifiable lifestyle factors; multiple omics; novel; novel strategies; novel therapeutics; pathogen; prevent; repository; side effect; statistics; therapy development; urogenital tract; vaginal dryness; vaginal lactobacilli; vaginal microbiota

Over 50% of postmenopausal women are affected by the genitourinary syndrome of menopause (GSM), a progressive, chronic condition related to estrogen decline that includes vaginal atrophy, vaginal dryness, reduced sexual desire, and other signs and symptoms. GSM symptoms are a costly public health concern and worsen if untreated. Estrogen decline in menopause is thought to lead to reduced accumulation of vaginal glycogen and shifts in vaginal microbiota. These include low vaginal Lactobacillus spp. levels in 50-80% of postmenopausal women. Lactobacillus spp. protect the urogenital tract from pathogens in part by lactic acid production and hypothesized anti-inflammatory properties, but whether lactobacilli 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 about side effects. While vaginal lubricants provide some relief, many are toxic to the vaginal epithelium, reduce lactobacilli, and raise urogenital infection risk. Thus, new ways to treat and prevent GSM are needed. Because lactobacilli are often reduced in menopause, vaginal microbiota are plausible treatment targets; however, probiotics alone have not been proven effective. Also, age-related changes in vaginal microbiota co-vary with metabolite and immune profiles; but, the cross- talk between these molecular features and their role in GSM is unknown. We hypothesize that core vaginal micro-environment biomarkers (VMB; e.g., microbial, metabolite, and immune profiles) reflect vaginal biological aging (V-BA) that increases in menopause but may be modifiable by lifestyle factors. Prospective studies are needed to identify core age-related VMB and determine how they affect GSM. To achieve this goal, we will leverage 2,301 archived cervicovaginal samples collected from 812 women aged 35-60 years with clinical 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). We will quantify concentrations of 70 immune markers (cytokines, chemokines, growth factors) and metabolites (GC/LC-MS) in cervicovaginal samples. A novelty of this proposed project is that we will develop, validate, and apply new statistical methods for complex longitudinal data that refine and adapt modern structural modeling and compositional microbiome data analyses. These methods will provide a rigorous framework to handle missing data and confounding that has been a major limitation in many microbiome studies. The ultimate public health impact is that findings from this project have potential to inform development of new therapy to prevent or treat GSM to promote women’s health. Our team has the expertise in biostatistics, epidemiology, aging, gynecology, genomics, microbiology, and immunology required for this 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，这是一种 与雌激素下降相关的进行性慢性疾病，包括阴道萎缩、阴道干燥、 性欲减退以及其他 GSM 症状是一个代价高昂的公共卫生问题。 如果不治疗，雌激素下降会导致阴道积聚减少。 糖原和阴道微生物群的变化，其中包括 50-80% 的阴道乳酸菌水平低。 绝经后妇女的乳酸菌可部分通过乳酸保护泌尿生殖道免受病原体侵害。 生产和突袭抗炎特性，但乳酸菌是否在其中发挥功能性作用 外阴阴道 GSM 症状的可用治疗方法尚不清楚，有些女性存在局限性。 禁忌激素治疗或担心副作用，而阴道润滑剂则可提供。 一些缓解措施，许多对阴道上皮有毒，减少乳酸杆菌，并增加泌尿生殖系统感染的风险。 因此，需要新的方法来治疗和预防 GSM，因为乳酸杆菌在更年期通常会减少。 阴道微生物群是合理的治疗目标；然而，单独使用益生菌尚未被证明有效。 此外，阴道微生物群与年龄相关的变化与代谢和免疫特征共同变化；但是， 这些分子特征及其在 GSM 中的作用之间的讨论尚不清楚。 微环境生物标志物（VMB；例如微生物、代谢物和免疫特征）反映阴道生物学 前瞻性研究表明，衰老（V-BA）在更年期会增加，但可能会受到生活方式因素的影响。 需要确定与年龄相关的核心 VMB 并确定它们如何影响 GSM 为了实现这一目标，我们将。 利用从 812 名 35-60 岁女性收集的 2,301 份宫颈阴道样本进行临床研究 两年内每六个月进行一次访问（R01-CA123467），具体目标是 1) 使用 VMB 量化 V-BA； 评估V-BA和GSM之间的纵向关系；3)纵向评估 生活方式因素对 V-BA 和 VMB 的影响；4) 量化 V-BA 和 VMB 在生活方式与 GSM. 微生物群已通过 16S rRNA 基因扩增子测序 (R21-AI107224) 进行了分析。 70 种免疫标记物（细胞因子、趋化因子、生长因子）和代谢物的定量浓度 （GC/LC-MS）在宫颈阴道样品中的应用 该拟议项目的新颖之处在于我们将开发、验证和分析。 对复杂的纵向数据应用新的统计方法，以完善和适应现代结构建模 这些方法将提供严格的框架来处理。 数据缺失和混淆一直是许多微生物组研究的主要限制。 健康影响在于，该项目的研究结果有可能为开发新疗法提供信息，以预防 或治疗 GSM 以促进女性健康。我们的团队拥有生物统计学、流行病学、老龄化等方面的专业知识。 这种 GSM 系统生物学方法所需的妇科、基因组学、微生物学和免疫学。