Unraveling mechanisms by which cervicovaginal microbiota can promote or prevent cervical remodeling and preterm birth

揭示宫颈阴道微生物群促进或预防宫颈重塑和早产的机制

• 批准号: 9886482
• 负责人: MICHAL Aviva ELOVITZ
• 金额: $ 68.5万
• 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: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9886482
• 关键词: Address; Automobile Driving; Bacteria; Biological Process; Biomechanics; Birth; Cancer Biology; Cervical; Cervix Uteri; Epithelial; Epithelial Cells; Epithelium; 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; Mucous Membrane; Mus; Pathogenesis; Placenta; Pregnancy; Pregnant Women; Premature Birth; Preventive; Process; Production; Proteomics; Scientist; Series; Structure; Study models; Techniques; Term Birth; Testing; Therapeutic; Time; Tissues; Uterus; Vagina; Work; 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

Summary: 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), 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.

摘要：每年，有1500万婴儿出生早。超过75％的早产（PTB）被称为 自发（SPTB）在妊娠时间点发生分娩而没有明显的原因。我们缺乏 了解促进SPTB的机制和整体发病机制导致成功的成功 干预措施。虽然子宫收缩性和宫颈重塑似乎是强制性的过程 分娩，这些过程的过早触发因素仍然很差。最近的研究揭示了关闭 宫颈阴道（CV）微生物群落与SPTB的发生之间的关联。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 怀孕初期的免疫反应，提供了有力的证据，表明特定细菌分类群定殖， 特定的代谢谱和局部免疫反应与SPTB密切相关。但是，要 制定预防或治疗策略，了解SPTB的原因是必不可少的。我们推测 CV微生物群落，局部免疫反应以及宫颈和阴道上皮之间的相互作用 障碍会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 特定的CV细菌如何在体外和体内与阴道和上皮细胞相互作用 模型并了解这些相互作用如何改变孕妇的组织重塑和生物力学 子宫颈，驾驶SPTB。我们提出了一个过程，使细菌分类单元与SPTB高度相关 人类会引起阴道上皮的去角质。该过程促进上皮 - 间质转变 （EMT）来自阴道和宫颈上皮细胞。而EMT的激活阻止了这些的提升 细菌，一种权衡是EMT促进了颈组织细胞外基质的分解，触发 过早的宫颈重塑和SPTB。因此，我们的中心假设是特定细菌，例如 gardnerella daginalis（g.vaginalis），促进阴道和宫颈上皮屏障的EMT，以改变 即使没有上升感染，孕妇子宫颈的结构和功能也导致SPTB （在子宫颈上方）。该范式转移假设将通过一系列体外和体内进行测试 实验。该提案将首先解决是否需要细菌升高到子宫中 为了使PTB发生；这些研究有可能重新构架我们的科学和治疗方法对PTB。 然后，我们将证明细菌如何在CV上皮屏障中诱导EMT以及EMT如何促进 过早的宫颈重塑。该提案独有的，我们将对 在PTB的小鼠模型中，就结构和功能而言，怀孕的子宫颈。一个多学科团队增加了 通过将新颖的概念和技术应用于SPTB的研究，使我们的工作严格。这些研究将提供 关于限制或防止SPTB的新的和专注的治疗目标的见解，并将大大推动这一点 场地。