Elucidating causes of vaginal symptoms using a multi-omics approach

使用多组学方法阐明阴道症状的原因

• 批准号: 9273625
• 负责人: LARRY J FORNEY
• 金额: $ 54.79万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-13 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273625
• 关键词: Address; Age; Anxiety; Archives; Bacterial Vaginosis; Behavior; Behavioral; Biological; Categories; Chronic; Communities; Cream; Data; Data Set; Diagnosis; Diagnostic Procedure; Discipline of obstetrics; Emotional; Endometritis; Environment; Equilibrium; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Gynecologic; Gynecology; HIV; Health; Health Care Visit; Homeostasis; Human Microbiome; Immune response; Immune system; Immunologic Factors; Knowledge; Lasso; Longitudinal Studies; Malignant neoplasm of cervix uteri; Manuals; Metadata; Microbe; Mission; Modeling; Modernization; Molecular Profiling; Natural Immunity; Odors; Outcome; Pathway Analysis; Pattern; Pelvic Inflammatory Disease; Powder dose form; Property; Pruritus; Public Health; Quality of life; Recovery; Recurrence; Reporting; Reproductive Health; Research; Research Design; Resort; Risk; Sampling; Severities; Sex Functioning; Sexual Transmission; Sexually Transmitted Diseases; Signs and Symptoms; Social Functioning; Social Impacts; Structure; Swab; Symptoms; Systems Biology; Techniques; Technology; Testing; Time; Translating; United States; United States National Institutes of Health; Vagina; Vaginal Discharge; Vaginal Douching; Woman; Women' s Health; Work; alternative treatment; associated symptom; causal model; chemokine; cost; cytokine; diaries; experience; immunological status; improved; irritation; medical attention; metabolome; metagenome; microbial; microbial host; microbiota; novel strategies; novel therapeutic intervention; nutrition; persistent symptom; personalized management; predictive marker; predictive modeling; predictive signature; prevent; prospective; public health relevance; repository; reproductive; self esteem; self help; transcriptome; vaginal microbiome

 DESCRIPTION (provided by applicant): Vaginal discharge, burning, itching, and malodor are the most common vaginal symptoms reported by reproductive-age women resulting in millions of health care visits annually in the United States alone. These symptoms create substantial discomfort, are often recurrent, and negatively impact women's self- esteem and quality of life. Often, women resort to ill-advised alternative treatments in an attempt to ameliorate their symptoms that only provide a short-lived relief, and in many cases increase symptom severity. These symptoms are associated with numerous serious gynecological and obstetric outcomes, including an increased risk for sexually transmitted infections. The long-term goal of the proposed work is to develop a more complete understanding of the underlying causes of vaginal symptoms so that targeted and effective strategies can be developed to effectively prevent or treat vaginal discharge, discomfort, and malodor. The multi-omics datasets we propose to gather and analyze will allow us to test the central hypothesis that symptoms are emergent properties of the vaginal microbiome that result from the interplay of specific functions, and not simply microbial composition of vaginal microbiomes and host responses elicit these signs and symptoms. To achieve this, we will leverage a unique set of vaginal swabs samples and extensive metadata that were prospectively collected daily by 135 women for 10 weeks. During this study, women experienced either 1) clear episodes of vaginal symptoms, 2) chronic and persistent symptoms or 3) no symptoms. The study design affords a unique opportunity to use `omics technologies on samples collected before, during and after episode of vaginal symptoms and compare these to women with chronic or no symptoms, and identify specific predictive biomarkers that will translate to more personalized management of women's health. The proposed project will address two specific aims: (1) Determine the composition and function of the vaginal microbiome by characterizing bacterial metagenomes, the host and bacterial transcriptomes and metabolomes, and markers of innate immunity in vaginal samples collected prior to, during and after episodes of vaginal symptoms and compare these to comparable data from asymptomatic women. (2) Develop predictive and causal models of symptom onset using integrative systems biology approaches using a multi- prong modeling strategy that includes lasso regression, ridge regression and elactic net regression combined with robust and modern model selection techniques, and network analyses, we will achieve a predictive and causal model that is a balance of robustness, explanatory power, and size (in terms of the number of predictor variables). Armed with detailed knowledge of changes in genomic factor of the microbiota and the host during the onset and recovery from vaginal symptoms it will be possible to develop more accurate and sensitive diagnostic procedures, new therapeutic strategies, and effective means to insure vaginal homeostasis.

 描述（由申请人提供）：阴道分泌物、烧灼感、瘙痒和恶臭是育龄妇女报告的最常见的阴道症状，仅在美国每年就有数百万人就诊。这些症状造成严重的不适，经常反复发作，并对妇女的自尊和生活质量产生负面影响。妇女往往求助于不明智的替代治疗，试图改善其症状，但这种治疗只能提供短暂的缓解，而且在许多情况下会增加症状的严重程度。这些症状与许多严重的妇科和产科结果有关，包括增加性传播感染的风险。拟议工作的长期目标是更全面地了解阴道症状的根本原因，以便制定有针对性的有效策略，以有效预防或治疗阴道分泌物，不适和恶臭。我们建议收集和分析的多组学数据集将使我们能够测试中心假设，即症状是由特定功能相互作用引起的阴道微生物组的新兴特性，而不仅仅是阴道微生物组的微生物组成和宿主反应引发这些体征和症状。为了实现这一目标，我们将利用一组独特的阴道拭子样本和广泛的元数据，这些样本和元数据是由135名女性每天前瞻性收集的，为期10周。在这项研究中，女性经历了1）明确的阴道症状发作，2）慢性和持续性症状或3）没有症状。这项研究设计提供了一个独特的机会，可以利用“组学”技术对阴道症状发作之前、期间和之后收集的样本进行分析，并将这些样本与有慢性症状或无症状的妇女进行比较，确定具体的预测性生物标志物，从而对妇女的健康进行更加个性化的管理。拟议的项目将解决两个具体目标：（1）通过表征细菌宏基因组，宿主和细菌转录组和代谢组以及在阴道症状发作之前，期间和之后收集的阴道样本中的先天免疫标记物来确定阴道微生物组的组成和功能，并将这些与无症状女性的可比数据进行比较。(2)使用综合系统生物学方法开发症状发作的预测和因果模型，使用多管齐下的建模策略，包括套索回归，岭回归和elactic net回归，结合稳健和现代模型选择技术和网络分析，我们将实现预测和因果模型，该模型是稳健性，解释力和大小（就预测变量的数量而言）的平衡。掌握了阴道症状发作和恢复期间微生物群和宿主基因组因子变化的详细知识，将有可能开发更准确和灵敏的诊断程序，新的治疗策略和确保阴道稳态的有效手段。