Molecular Epidemiology of the Vaginal Microbiome

描述(申请人提供)：候选人：丽贝卡·布罗特曼博士是马里兰大学医学院基因组科学研究所和流行病学与预防医学系的助理教授。这一职业发展奖将允许应聘者将她的培训从经典流行病学扩展到元基因组数据的分析和翻译。候选人将在获奖期结束时接受独特的培训，以便将微生物组数据整合到分子流行病学研究中。 背景：阴道微生物区系在维护女性健康方面起着重要的保护作用。破坏阴道内细菌群落和宿主之间存在的互惠关系可能会导致细菌性阴道病(BV)，在这种情况下，产生乳酸菌被各种严格厌氧细菌取代。在流行病学方面，BV已被证明是不良结局的独立危险因素，包括早产、获得性传播感染和艾滋病毒以及发展成盆腔炎。全国调查表明，BV在美国女性中的患病率为29%，然而，尽管做出了相当大的努力，BV的原因仍不清楚。此外，目前还没有广泛有效的治疗BV的方法，而且复发很常见。该项目的总体目标是通过将对BV危险因素的流行病学研究与对阴道微生物区系的基因组研究相结合来更好地定义BV，以寻找调节发病和缓解的机制。 方法：我们将利用39名妇女每周两次收集的存档阴道拭子，进行为期16周的前瞻性研究(1107份样本)。这些标本捕捉了在BV发作自发缓解之前、期间和之后以及在月经周期的时间过程中发生的分子事件。我们将在分析从阴道拭子中分离的全基因组DNA中扩增出的16S rRNA基因序列的基础上，应用与培养无关的方法。这些标本为研究四个特定目标提供了独特的机会：1)表征阴道微生物群落结构(物种组成和等级丰度)随时间的变化；2)开发诊断BV的分子模型；3)应用基于模型的统计方法来评估时变因素与行为与微生物群落组成变化之间的关系；以及4)评估停止阴道冲洗对阴道微生物区系的影响。 意义：目前，对BV的诊断尚无分子成分。在这项研究中使用现代元基因组技术将使我们能够识别阴道微生物群落和模式，这些微生物群落和模式可以预测BV。拟议的研究将促进我们对阴道微生物区系的了解，推动BV诊断工具的开发，并可能导致改进预防和治疗BV的方法。细菌性阴道病(BV)是女性最常见的阴道疾病，其病因和有效的治疗方法尚不清楚。BV与许多不利的健康后果有关，例如早产低出生体重婴儿和增加感染艾滋病毒的风险。这项研究将有助于提供有关BV病因的有价值的信息，有助于开发改进的BV诊断、预防和治疗方法，并可能有助于减少与BV相关的主要生殖健康问题。

DESCRIPTION (provided by applicant): Candidate: Dr. Rebecca Brotman is an Assistant Professor with the Institute for Genome Sciences and the Department of Epidemiology and Preventive Medicine at the University of Maryland School of Medicine. This career development award would allow the candidate to expand her training from classical epidemiology to the analysis and translation of metagenomic data. The candidate will be uniquely trained by the end of the award period to integrate microbiome data in molecular epidemiological studies. Background: Vaginal microbiota play an important protective role in maintaining the health of women. Disruption of the mutualistic relationship that exists between bacterial communities in the vagina and their hosts can lead to bacterial vaginosis (BV), a condition in which lactic acid-producing bacteria are supplanted by a diverse array of strictly anaerobic bacteria. Epidemiologically, BV has been shown to be an independent risk factor for adverse outcomes including preterm birth, acquisition of sexually transmitted infections and HIV, and development of pelvic inflammatory disease. National surveys indicate the prevalence of BV among U.S. women is 29%, and yet, despite considerable effort, the cause of BV remains unknown. Moreover, there are no broadly effective therapies for the treatment of BV and recurrence is common. The overarching goal of this project is to better define BV by linking epidemiologic research on risk factors for BV with genomic research on vaginal microbiota to search for the mechanisms that mediate onset and remission. Methods: We will utilize archived vaginal swabs which were collected twice-weekly by 39 women in a 16-week prospective study (1,107 samples). The specimens capture molecular events that take place before, during, and after the spontaneous remission of BV episodes and over the time course of the menstrual cycle. We will apply cultivation-independent methods based on the analysis of 16S rRNA gene sequences amplified from whole genomic DNA isolated from the vaginal swabs. The specimens provide a unique opportunity to investigate four specific aims: 1) Characterize the changes in structure (species composition and rank abundance) of vaginal microbial communities over time; 2) Develop a molecular model for the diagnosis of BV; 3) Apply model-based statistical approaches to evaluate the relationship between time-varying factors and behaviors with shifts in microbial community composition; and 4) Evaluate the effect of vaginal douching cessation on the vaginal microbiota. Significance: Currently, there is no molecular component to the diagnosis of BV. Use of modern metagenomic technologies in this study will allow us to identify vaginal microbial communities and patterns that are predictive of BV. The proposed studies will facilitate our understanding of vaginal microbiota, drive the development of diagnostic tools for BV and may lead to improved methods for preventing and treating BV. Bacterial vaginosis (BV) is the most common vaginal disease in women, and yet its cause and effective treatment remain unknown. BV is associated with many adverse health outcomes, such as preterm delivery of low birth weight babies and increased risk for infection by HIV. This research will contribute valuable information on the causes of BV, help develop improved methods for diagnosing, preventing and treating BV, and may help reduce major reproductive health problems associated with BV.