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）每年影响全球1500万儿童， 婴儿死亡率和幸存者终身健康并发症的可能性。一个不完整 对导致早产的危险因素的理解限制了早期， 准确评估PTB风险以及预防治疗。我们最近的研究 强调了宫颈上皮在提供屏障和免疫方面的重要作用， 保护在怀孕期间，并导致确定“宫颈上皮功能障碍”作为一个 早产的新危险因素。在怀孕和分娩期间，上皮细胞必须 增殖，分化，形成连接和粘膜屏障，以保护生殖 上行感染和由此导致的早产风险。怀孕期间，这些 上皮细胞的责任部分由细胞外基质信号调节，特别是由 增加糖胺聚糖透明质酸（HA）的合成。缺乏HA合成的小鼠， 子宫颈显示异常上皮分化、增加的上皮和粘膜 渗透性和上升感染引起的PTB率增加。的增加 妊娠晚期宫颈透明质酸受透明质酸合成酶2的调节 （Has 2）基因表达。因此，本研究的重点是理解i）通过以下方式的机制： HA参与宫颈上皮能力，ii）鉴定下游转录组 HA的靶点和iii）了解宫颈中Has 2表达的转录调控。 我们将检验HA维持宫颈上皮屏障功能的能力 免疫保护需要与HA相互作用蛋白相互作用， 参与上皮分化、屏障功能和对Toll样受体应答的过程 发信号。