Deciphering the Role of Vaginal Microbes in Preterm birth

解读阴道微生物在早产中的作用

• 批准号: 10249230
• 负责人: MICHAL Aviva ELOVITZ
• 金额: $ 65.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10249230
• 关键词: Address; Automobile Driving; Bacteria; Biological Process; Biomechanics; Birth; Cancer Biology; Cervical; Cervix Uteri; Epithelial; Epithelial Cells; Etiology; Extracellular Matrix; Fetal Membranes; Fibrosis; Fostering; Gardnerella vaginalis; Gelatinase B; Germ-Free; Goals; Human; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Knowledge; Lead; Measures; Mesenchymal; Metabolic; Microbe; Mobiluncus mulieris; Mucous Membrane; Mus; Pathogenesis; Pregnancy; Pregnant Women; Premature Birth; Preventive; Process; Production; Proteomics; Reporting; Reproducibility; Role; Scientist; Series; Structure; Study models; Techniques; Term Birth; Testing; Therapeutic; Time; Tissues; Uterus; Vagina; Work; cervical remodeling; cervicovaginal; clinically relevant; cohort; commensal bacteria; experimental study; fetal; in vivo; in vivo Model; innovation; insight; intraamniotic infection; metabolic profile; microbial community; microbiota; mouse model; multidisciplinary; new therapeutic target; novel; pregnant; premature; prevent; protease E; reproductive tract; response; successful intervention; therapeutic target; uterine contractility; vaginal infection

Every year, 15 million babies are born premature. Over 75% of preterm births (PTBs) are termed spontaneous (sPTB) resulting in parturition at early gestational time points without clear causes. Our lack of understanding of the mechanisms and overall pathogenesis that promotes sPTB results in limited successful interventions. While uterine contractility and cervical remodeling appear to be obligatory processes in parturition, premature triggers of these processes remain poorly elucidated. Recent studies reveal close associations between cervicovaginal (CV) microbial communities and the occurrence of sPTB. In particular, we recently studied a cohort of 2000 pregnant women and assessed the CV microbial communities, metabolic and immune responses early in pregnancy, providing strong evidence that colonization with specific bacterial taxa, specific metabolic profiles, and local immune responses were strongly associated with sPTB. However, to develop preventive or therapeutic strategies, understanding the cause of sPTB is essential. We speculate that interplay between the CV microbial communities, local immune response and the cervical and vaginal epithelial barriers induce premature cervical remodeling and initiate sPTB. The overall goal of this study is to define how specific CV bacteria interact with vaginal and epithelial cells in clinically relevant in vitro and in vivo models and to understand how those interactions modify tissue remodeling and biomechanics of the pregnant cervix, driving sPTB. We propose a process whereby bacterial taxa that are highly associated with sPTB in humans provoke exfoliation of the vaginal epithelium. This process promotes epithelial-mesenchymal transition (EMT) from both vaginal and cervical epithelial cells. While activation of EMT prevents the ascension of these bacteria, a tradeoff is that EMT fosters breakdown of the extracellular matrix in the cervical tissue, triggering premature cervical remodeling and sPTB. Therefore, our central hypothesis is that specific bacteria, such as Gardnerella vaginalis (G.vaginalis) and Mobiluncus mulieris (M. Mulieris), promote EMT of the vaginal and cervical epithelial barrier which alters the structure and function of the pregnant cervix, leading to sPTB, even in the absence of ascending infection (above the cervix). This paradigm-shifting hypothesis will be tested through a series of in vitro and in vivo experiments. This proposal will first address whether ascension of bacteria into the uterus is actually necessary for PTB to occur; these studies have the potential to reframe our scientific and therapeutic approach to PTB. We will then demonstrate how bacteria induce EMT in CV epithelial barriers and how EMT might promote premature cervical remodeling. Unique to this proposal, we will provide quantitative assessment of the pregnant cervix, in terms of structure and function, in a mouse model of PTB. A multidisciplinary team adds rigor to our work by applying novel concepts and techniques to the study of sPTB. These studies will provide insight as to new and focused therapeutic targets to limit or prevent sPTB and will significantly advance this field.

每年，1500万婴儿出生早。超过75％的早产（PTB）被称为自发性 （SPTB）在妊娠时间点发生分娩，没有明确的原因。我们缺乏理解 促进SPTB的机制和总体发病机制导致成功的干预措施有限。 虽然子宫收缩力和宫颈重塑似乎是强制性的过程，但过早 这些过程的触发因素仍然很差。最近的研究揭示了之间的密切关联 宫颈阴道（CV）微生物群落和SPTB的发生。特别是，我们最近研究了 2000名孕妇的队列，并评估了CV微生物群落，代谢和免疫 怀孕初期的反应，提供了有力的证据，表明特定细菌分类群定植 代谢谱和局部免疫反应与SPTB密切相关。但是，要发展 预防或治疗策略，了解SPTB的原因至关重要。我们推测该相互作用 在CV微生物群落，局部免疫反应以及宫颈和阴道上皮屏障之间 诱导过早的宫颈重塑并启动SPTB。这项研究的总体目标是定义如何具体 CV细菌与临床相关的体外和体内模型中的阴道和上皮细胞相互作用，以及 了解这些相互作用如何改变怀孕子宫颈的组织重塑和生物力学，驱动 SPTB。我们提出了一个过程，使人类与SPTB高度相关的细菌分类群 阴道上皮的角质。该过程促进了两者的上皮 - 间质转变（EMT） 阴道和宫颈上皮细胞。尽管EMT的激活阻止了这些细菌的提升，但 权衡是EMT促进了颈组织中细胞外基质的分解，从而触发过早 宫颈重塑和SPTB。因此，我们的中心假设是特定细菌，例如 gardnerella vaginalis（g.vaginalis）和mobiluncus mulieris（M。mulieris），促进阴道和 宫颈上皮屏障会改变孕妇子宫颈的结构和功能，从而导致SPTB，甚至 在没有上升感染的情况下（子宫颈上方）。将测试此范式转移假设 通过一系列体外和体内实验。该提议将首先解决是否提升 实际上，PTB发生的细菌实际上是必需的。这些研究有可能重塑我们的 PTB的科学和治疗方法。然后，我们将证明细菌如何在CV上皮诱导EMT 障碍以及EMT如何促进过早的宫颈重塑。该提议独有的，我们将提供 在PTB的小鼠模型中，在结构和功能方面对怀孕子宫颈的定量评估。一个 多学科团队通过将新颖的概念和技术应用于SPTB的研究来增加我们的工作。 这些研究将提供有关新的且重点的治疗靶标，以限制或防止SPTB的见解，并将 显着推进了这一领域。