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％的绝经后妇女受到泌尿生殖器综合征（GSM）的影响，A 进行性，慢性病与雌激素下降有关，包括阴道萎缩，阴道干燥， 减少了性欲以及其他体征和症状。 GSM符号是一个昂贵的公共健康问题， 如果未治疗，会恶化。人们认为更年期的雌激素下降会导致阴道积累减少 糖原和阴道微生物群的转移。这些包括低阴道乳酸杆菌属。 50-80％的水平 绝经后妇女。乳杆菌属。乳酸部分保护泌尿生殖道免受病原体的侵害 生产和假设的抗炎特性，但是乳酸杆菌是否在 GSM未知。外阴阴道GSM符号的可用处理有局限性。有些女人是 禁忌进行荷尔蒙治疗或关注副作用。而阴道润滑剂提供 一些缓解，许多对阴道上皮有毒，减少乳杆菌并增加泌尿生殖感染的风险。 这是需要新的治疗和预防GSM的方法。因为乳酸杆菌经常在更年期中降低，所以 阴道菌群是合理的治疗靶标。但是，仅益生菌尚未被证明有效。 同样，与代谢物和免疫特征共同变化的阴道微生物群的变化；但是，十字架 - 这些分子特征与它们在GSM中的作用之间的交谈尚不清楚。我们假设该核心阴道 微环境生物标志物（VMB；例如微生物，代谢物和免疫谱）反映了阴道生物学 衰老（V-BA）增加了更年期，但可能会因生活方式因素而改变。前瞻性研究是 需要识别与年龄相关的VMB并确定它们如何影响GSM。为了实现这一目标，我们将 杠杆率为2,301个存档的宫颈阴道样品，从35-60岁的812名女性收集 每六个月访问两年（R01-CA123467）。具体目的是使用VMB量化V-BA； 2） 评估V-BA和GSM之间的纵向关系； 3）纵向评估 V-BA和VMB的生活方式因素； 4）通过V-BA和VMB量化生活方式和VMB的纵向调解 GSM。微生物群已经由16S rRNA基因扩增子测序（R21-AI107224）进行了分析。我们将 定量70种免疫标记物（细胞因子，趋化因子，生长因子）和代谢产物的浓度 （GC/LC-MS）在宫颈阴道样品中。这个拟议项目的新颖性是我们将开发，验证和 将新的统计方法应用于完善和适应现代结构建模的复杂纵向数据 和复合微生物组数据分析。这些方法将提供一个严格的框架来处理 在许多微生物组研究中，缺少数据和混淆一直是一个主要局限性。最终的公众 健康的影响是，该项目的发现有可能为开发新疗法提供信息 或治疗GSM以促进妇女健康。我们的团队在生物统计学，流行病学，衰老， 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。