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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

基本信息

批准号：
10800388
负责人：
MICHAL Aviva ELOVITZ
金额：
$ 54.06万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10800388
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 Mucous Membrane Mus Pathogenesis Peptide Hydrolases 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 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

项目摘要

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 万婴儿早产。超过 75% 的早产 (PTB) 被称为足月儿自发性（sPTB）导致在没有明确原因的情况下在妊娠早期分娩。我们缺乏对促进 sPTB 的机制和总体发病机制的了解导致有限的成功干预措施。虽然子宫收缩和宫颈重塑似乎是女性的必经过程分娩、这些过程的过早触发因素仍然知之甚少。最近的研究表明接近宫颈阴道 (CV) 微生物群落与 sPTB 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、代谢和怀孕早期的免疫反应，提供了强有力的证据表明特定细菌类群的定植，特定的代谢特征和局部免疫反应与 sPTB 密切相关。然而，为了制定预防或治疗策略，了解 sPTB 的病因至关重要。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导致宫颈过早重塑并引发 sPTB。本研究的总体目标是定义特定CV细菌如何在临床相关的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，驱动 SPTB。我们提出了一个过程，通过该过程，与 sPTB 高度相关的细菌类群人类会引起阴道上皮的剥落。该过程促进上皮间质转化 (EMT) 来自阴道和宫颈上皮细胞。虽然 EMT 的激活会阻止这些物质的提升细菌，一个权衡是 EMT 会促进宫颈组织中细胞外基质的分解，引发宫颈早期重塑和 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)，促进阴道和宫颈上皮屏障的 EMT，从而改变妊娠子宫颈的结构和功能，即使没有上行感染，也会导致 sPTB （子宫颈上方）。这一范式转变的假设将通过一系列体外和体内试验进行检验实验。该提案将首先解决细菌上升到子宫是否确实必要的问题导致 PTB 发生；这些研究有可能重塑我们治疗肺结核的科学和治疗方法。然后我们将演示细菌如何在 CV 上皮屏障中诱导 EMT 以及 EMT 如何促进过早的宫颈重塑。本提案的独特之处在于，我们将提供定量评估 PTB 小鼠模型中妊娠子宫颈的结构和功能。多学科团队补充道通过将新颖的概念和技术应用于 SPTB 的研究来严格我们的工作。这些研究将提供关于限制或预防 sPTB 的新的、有针对性的治疗靶点的见解，并将显着推进这一目标场地。