Mechanisms of Cervical Epithelial Barrier Protection Against Ascending Infection and Preterm Birth

宫颈上皮屏障预防上行感染和早产的机制

• 批准号: 10063455
• 负责人: MALA S. MAHENDROO
• 金额: $ 26.35万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063455
• 关键词: Adhesions; Affect; Animal Model; Bacterial Infections; Binding; Biochemical; Bioinformatics; Biology; Birth; Birth Rate; Blocking Antibodies; CD44 gene; Cell Line; Cell Separation; Cells; Cellular biology; Cervical; Cervix Uteri; ChIP-seq; Child; Competence; Cues; Cytoskeletal Modeling; DNase I hypersensitive sites sequencing; Data Set; Defect; Dependence; Detection; Development; EGF gene; Enhancers; Ensure; Epithelial; Epithelial Cells; Escherichia coli; Exposure to; Extracellular Matrix; Extracellular Protein; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomic approach; Genomics; Glycosaminoglycans; HAS2 gene; Health; Human; Hyaluronan; Hyaluronidase; Immune; Infant Mortality; Infection; Innate Immune Response; Knockout Mice; Late pregnancy; Lead; Ligands; Maintenance; Maternal-Fetal Exchange; Mediating; Mediator of activation protein; Molecular; Mucous Membrane; Mus; Permeability; Play; Predisposition; Pregnancy; Premature Birth; Prevention therapy; Process; Proliferating; Proteins; Proteoglycan; Receptor Signaling; Regulation; Risk; Risk Factors; Role; Signal Pathway; Survivors; Testing; Time; Tissues; Toll-like receptors; Transcriptional Regulation; Validation; Viral; Virus Diseases; Wild Type Mouse; cervical remodeling; cervicovaginal; fibromodulin; fighting; genome-wide; improved; insight; novel therapeutics; pregnant; premature; reproductive tract; response; therapeutic target; tool; tool development; transcription factor; transcriptome; transcriptome sequencing; versican

Abstract- Mahendroo Preterm birth (PTB) affects 15 million children world-wide annually contributing significantly to infant mortality and the potential for lifelong health complications in survivors. An incomplete understanding of risk factors that lead to preterm birth has limited development of tools for early, accurate assessment of PTB risk as well as therapies for prevention. Our recent studies have highlighted the important role that the cervical epithelia play in providing barrier and immune protection during pregnancy and led to the identification of “cervical epithelial dysfunction” as a new risk factor for preterm birth. Through pregnancy and parturition, the epithelia must proliferate, differentiate, and form a junctional and mucosal barrier to protect the reproductive tract from ascending infection and resulting risk of preterm birth. During pregnancy these epithelial responsibilities are regulated in part by extracellular matrix cues, specifically by the increased synthesis of the glycosaminoglycan hyaluronan (HA). Mice lacking HA synthesis in the cervix display abnormal epithelial differentiation, increased epithelial and mucosal permeability and increased PTB rates in response to ascending infection. The increase in cervical hyaluronan during late pregnancy is regulated by increased hyaluronan synthase 2 (Has2) gene expression. The focus of this study is thus to understand i) the mechanism by which HA participates in cervical epithelial competency, ii) identify downstream transcriptome targets of HA and iii) understand the transcriptional regulation of Has2 expression in the cervix. We will test the overall hypothesis that HA’s ability to maintain epithelial cervical barrier function and immune-protection requires interactions with HA-interacting proteins and mediates processes involved in epithelial differentiation, barrier function and response to toll-like receptor signaling.

摘要 - Mahendroo 早产（PTB）每年在全球范围内影响1500万儿童 婴儿死亡率和生存中终身健康并发症的潜力。不完整 了解导致早产的危险因素的早期工具的开发有限， 准确评估PTB风险以及预防疗法。我们最近的研究已经 强调了宫颈上皮在提供障碍和免疫力中扮演的重要作用 怀孕期间的保护并导致“宫颈上皮功能障碍”鉴定为 早产的新风险因素。通过怀孕和分娩，上皮必须 扩散，区分并形成一个连接和粘膜屏障，以保护生殖 由于感染的上升和早产风险而导致的道路。在怀孕期间 上皮责任部分由细胞外基质提示，特别是由 糖胺聚糖透明质酸（HA）的合成增加。缺乏HA合成的小鼠 子宫颈显示异常上皮分化，上皮和粘膜增加 渗透性和PTB速率增加了上升感染的速率。增加 怀孕后期宫颈透明质酸受透明质酸合酶2的调节 （HAS2）基因表达。因此，这项研究的重点是了解i） 哪些参与者参与宫颈上皮能力，ii）识别下游转录组 HA和III的靶标）了解子宫颈中HAS2表达的转录调节。 我们将测试HA维持上皮宫颈屏障功能的能力的总体假设 免疫保护需要与HA相互作用的蛋白质和培养基相互作用 涉及上皮分化，障碍功能和对收费接收器的响应的过程 信号。