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

母胎界面的旁分泌控制对妊娠健康至关重要

基本信息

批准号：
10753130
负责人：
Sam Antonio MESIANO
金额：
$ 59.78万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2023-09-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753130
关键词：
37 weeks gestation Address Affect Anti-Inflammatory Agents Back Birth Cell Culture Techniques Cells Chorion Data Decidua Development Enzymes Event Feedback Feeds Fetal Membranes Genetic Granulocyte-Macrophage Colony-Stimulating Factor Hemorrhage Hormones Human Induced Labor Infant Mortality Infection Inflammation Inflammation Mediators Inflammatory Knowledge Labor Onset Link Maternal-Fetal Exchange Mechanics Mediating Metabolism Methods Modeling Molecular Neonatal Mortality Nuclear Pathway interactions Pregnancy Pregnancy Maintenance Premature Birth Process Production Progesterone RU-5020 Regulation Research Research Personnel Risk Rupture Signal Pathway Signal Transduction Stimulus Stromal Cells System Testing Therapeutic Tissues Water Withdrawal Work amnion clinically significant cytokine cytotrophoblast decidua parietalis effective therapy infant morbidity/mortality innovation myometrium neonatal morbidity new therapeutic target novel paracrine premature prevent receptor response steroid hormone therapy development trophoblast

项目摘要

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.

项目概要/摘要早产（<37 完整妊娠周）分娩 (PTB) 是导致新生儿死亡和发病的主要原因。大约 50% 的 PTB 与早产（即临产前）胎儿衰弱和破裂有关膜（FM：羊膜-绒毛膜-顶蜕膜）（pPROM）。感染/炎症和蜕膜出血是 pPROM 的主要驱动程序。预防 pPROM 和 PTB 的疗法的开发因了解在 FM 中面对炎症和出血挑战时如何维持妊娠。这拟议的研究建立在我们之前的研究基础上，研究了炎症刺激增加的机制削弱 FM 带来的 pPROM 风险，以及我们的黄体酮 (P4) 预防炎症的证明- 引起的调频减弱。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 是炎症和出血引起的 FM 减弱的关键中间体。重要的是，我们发现 P4 可以阻止 DS 细胞产生 GM-CSF。最近我们发现 GM-CSF 此外，引发一系列导致 FM 减弱的事件，诱导 FM 内 P4 的产生。基于根据这些数据，我们假设 FM 内存在局部作用、旁分泌、负反馈系统，从而 GM-CSF 响应局部炎症和出血刺激而产生，诱导邻近细胞产生 P4 绒毛膜细胞滋养层（CTB）细胞。 P4 反过来抑制 DS 细胞产生 GM-CSF，并且 GM-CSF- 引起的调频减弱。我们最近的发现支持了这一假设，即阻断 P4 的产生或作用每个独立地削弱 FM。因此，本地产生和本地发挥作用的 P4 对于维持 FM 的结构完整性。这一新颖且具有开创性的假设将通过实现两个具体目标来进行检验目的：1) 确定 GM-CSF 增加 CTB 细胞 P4 产生的信号通路，以及这是否 P4 产量下降与足月时 FM 减弱和 pPROM 相关，2) 确定机制 P4 通过其在 DS 细胞中发挥抗炎活性。实现具体目标将提供更多实质性了解 P4 在人类母胎界面的功能，以维持人类妊娠并预防 pPROM。了解这个过程对于开发有效的疗法来预防或至少很重要降低 pPROM 诱发早产的风险。