Paracrine control of the maternal-fetal interface critical for pregnancy wellness

项目总结/摘要 早产（<37完整孕周）是新生儿死亡和发病的主要原因。 大约50%的PTB与早产有关（即，临产前）胎儿虚弱和破裂 胎膜（FM：绒毛膜-壁蜕膜）（pPROM）。感染/炎症和蜕膜出血是 pPROM的主要驱动因素。预防胎膜早破和肺结核的治疗方法的开发受到以下方面差距的混淆： 了解如何在面对炎症和出血的挑战，在FM怀孕维持。的 这项研究建立在我们先前的工作基础上，研究了炎症刺激增加的机制。 通过削弱FM来降低胎膜早破的风险，我们证明孕酮（P4）可以预防炎症- 导致FM衰减。使用我们的离体FM外植体模型，我们发现炎症刺激通过以下方式削弱FM： 诱导蜕膜基质（DS）细胞产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）。 我们的研究表明GM-CSF是炎症和出血诱导的FM减弱的关键中间体。 重要的是，我们发现P4阻止DS细胞产生GM-CSF。最近我们发现，GM-CSF，在 此外，启动导致FM减弱的级联事件，诱导FM内的P4产生。基于 根据这些数据，我们假设FM中存在一个局部作用的旁分泌负反馈系统， 对局部炎症和出血刺激产生的GM-CSF诱导邻近细胞产生P4， 绒毛膜细胞滋养层（CTB）细胞。反过来，P4抑制DS细胞产生GM-CSF，并抑制GM-CSF。 导致FM衰减。我们最近的发现支持了这一假设，阻断P4的产生或作用， 每个独立地削弱FM。因此，本地生产和本地代理的P4对于维持 FM的结构完整性。这一新颖而开创性的假设将通过实现两个特定的 目的：1）鉴定GM-CSF通过其增加CTB细胞的P4产生的信号传导途径，以及这是否 P4产量下降与FM减弱在任期和pPROM，和2）确定的机制 P4通过该途径在DS细胞中发挥抗炎活性。实现具体目标将提供更多实质性的 了解P4在人类母胎界面的功能，以维持人类妊娠和预防 pPROM。了解这一过程对于开发有效的治疗方法以预防或至少 降低pPROM诱导早产的风险。

PROJECT SUMMARY/ABSTRACT Preterm (<37 completed weeks of gestation) birth (PTB) causes the majority of neonatal mortality and morbidity. Around 50% of PTBs are associated with preterm premature (i.e., pre-labor) weakening and rupture of the fetal membranes (FM: amnion-chorion-decidua parietalis) (pPROM). Infection/inflammation and decidual bleeding are major drivers of pPROM. Development of therapies to prevent pPROM and PTB are confounded by gaps in understanding how pregnancy is maintained in the face of inflammatory and bleeding challenges at the FM. The proposed research builds on our previous work examining the mechanisms by which inflammatory stimuli increase risk for pPROM by weakening the FM, and our demonstration that progesterone (P4) prevents inflammation- induced FM weakening. Using our ex-vivo FM explant model, we found that inflammatory stimuli weaken FM by inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) production by decidual stromal (DS) cells. Our studies suggest GM-CSF is a critical intermediate in both inflammation- and bleeding-induced FM weakening. Importantly, we found that P4 prevents GM-CSF production by DS cells. Recently we found that GM-CSF, in addition initiating a cascade of events which cause FM weakening, induces P4 production within the FM. Based on those data, we hypothesize that a locally-acting, paracrine, negative-feedback system exists within the FM, whereby GM-CSF produced in response to localized inflammatory and bleeding stimuli induces P4 production by adjacent chorion cytotrophoblast (CTB) cells. The P4, in turn, inhibits GM-CSF production by the DS cells and GM-CSF- induced FM weakening. This hypothesis is supported by our recent finding that blocking P4 production or action each independently weakens the FM. Thus, locally produced and locally acting P4 is essential for maintaining the structural integrity of the FM. This novel and groundbreaking hypothesis will be tested by achieving two Specific Aims: 1) identify the signaling pathway by which GM-CSF increases P4 production by CTB cells and whether this P4 production declines in association with FM weakening at term and pPROM, and 2) determine the mechanism by which P4 exerts anti-inflammatory activity in DS cells. Achieving the Specific Aims will provide more substantive understanding of P4 function at the human maternal-fetal interface to maintain human pregnancy and prevent pPROM. Understanding this process is important for development of effective therapies to prevent, or at least decrease, the risk for pPROM-induced preterm birth.