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

抽象--马亨德罗 早产(PTB)每年影响全球1500万儿童，对 婴儿死亡率和幸存者终身健康并发症的可能性。一个不完整的 对导致早产的风险因素的了解限制了早期工具的开发， 准确评估肺结核风险以及预防的治疗方法。我们最近的研究表明 强调宫颈上皮在提供屏障和免疫方面的重要作用 在怀孕期间的保护，并导致确定“宫颈上皮功能障碍”为 早产的新危险因素。在怀孕和分娩过程中，上皮细胞必须 增殖、分化并形成连接和粘膜屏障，以保护生殖 避免上行性感染和由此产生的早产风险。在怀孕期间这些 上皮细胞的职责部分受细胞外基质信号的调节，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 宫颈上皮细胞分化异常，上皮和粘膜增多。 通透性和肺结核发病率增加，以应对上升的感染。这一增长 妊娠晚期宫颈透明质酸受透明质酸合成酶2升高的调节 (HAS2)基因表达。因此，这项研究的重点是通过以下方式了解i)机制 哪些HA参与宫颈上皮细胞的功能，II)确定下游转录组 HA和III的靶标)了解Has2在宫颈表达的转录调控。 我们将检验总体假设，即HA维持宫颈上皮屏障功能的能力 免疫保护需要与透明质酸相互作用的蛋白质和介体相互作用 上皮分化、屏障功能和对Toll样受体反应的过程 发信号。

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.