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: 10091738
• 负责人: REBECCA M. BROTMAN
• 金额: $ 66.04万
• 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/10091738
• 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; 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; Structure; 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%的绝经后妇女受到更年期泌尿生殖系统综合征（GSM）的影响