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: 10647700
• 负责人: MICHAL Aviva ELOVITZ
• 金额: $ 68.92万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647700
• 关键词: Address; Automobile Driving; Bacteria; Biological Process; Biomechanics; Birth; Cancer Biology; Cervical; Cervix Uteri; 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; Measures; Mesenchymal; Metabolic; Microbe; Mobiluncus mulieris; Mucous Membrane; Mus; Pathogenesis; Peptide Hydrolases; 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; 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.

每年有 1500 万婴儿早产。超过 75% 的早产 (PTB) 被称为自然早产 (sPTB) 导致在没有明确原因的情况下在妊娠早期分娩。我们缺乏理解 促进 sPTB 的机制和总体发病机制导致干预措施的成功率有限。 虽然子宫收缩和宫颈重塑似乎是分娩过程中的必然过程，但早产 这些过程的触发因素仍不清楚。最近的研究揭示了两者之间的密切联系 宫颈阴道 (CV) 微生物群落和 sPTB 的发生。特别是，我们最近研究了一个 研究人员对 2000 名孕妇进行了队列研究，评估了 CV 微生物群落、代谢和免疫 怀孕早期的反应，提供了强有力的证据，表明特定细菌类群的定植、特定 代谢特征和局部免疫反应与 sPTB 密切相关。然而，要发展 预防或治疗策略中，了解 sPTB 的病因至关重要。我们推测相互作用 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的关系 诱导宫颈过早重塑并启动 sPTB。本研究的总体目标是确定具体如何 在临床相关的体外和体内模型中，CV细菌与阴道和上皮细胞相互作用，并 了解这些相互作用如何改变妊娠子宫颈的组织重塑和生物力学，推动 sPTB。我们提出了一个过程，通过该过程，与人类 sPTB 高度相关的细菌类群会引发 阴道上皮脱落。该过程促进上皮-间质转化（EMT） 阴道和宫颈上皮细胞。虽然 EMT 的激活可以防止这些细菌的繁殖， 权衡是，EMT 会促进宫颈组织细胞外基质的分解，引发早产 宫颈重塑和 sPTB。因此，我们的中心假设是特定细菌，例如 阴道加德纳菌 (G.vaginalis) 和穆里氏动链菌 (M. Mulieris)，促进阴道的 EMT 宫颈上皮屏障改变了妊娠子宫颈的结构和功能，导致 sPTB，甚至 在没有上行感染（子宫颈上方）的情况下。这种范式转变的假设将得到检验 通过一系列体外和体内实验。该提案将首先解决是否提升 细菌进入子宫实际上是 PTB 发生所必需的；这些研究有可能重塑我们的 PTB 的科学和治疗方法。然后我们将演示细菌如何诱导 CV 上皮细胞发生 EMT 障碍以及 EMT 如何促进宫颈过早重塑。本提案的独特之处在于，我们将提供 在 PTB 小鼠模型中对怀孕子宫颈的结构和功能进行定量评估。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，增加了我们工作的严谨性。 这些研究将为限制或预防 sPTB 的新的、有针对性的治疗靶点提供见解，并将 显着推进这一领域。