Effect of fetal exposure to maternal inflammation on offspring Paneth cell development and homeostasis

绒毛膜羊膜炎并发多达70%的早产儿，其特征是急性炎症。 胎盘/胎儿单位，使胎儿暴露在严重的炎症中。这些婴儿患癌症的风险增加。 涉及包括肠道在内的多个器官系统的短期和长期疾病。然而， 胎儿暴露于母体炎症(FEMI)导致不良结局的机制仍然存在 不清楚。我们的初步和已发表的数据表明，白介素6(IL-6)依赖的潘氏细胞丢失 导致与FEMI相关的肠道损伤易感性。我们的数据表明，Femi导致：IL-6- 依赖潘氏细胞丢失；血清炎症细胞因子基线水平持续升高，包括 IL-6；临床相关的肠道损伤；以及对继发性肠道损伤的易感性增加。然而， 这些效应背后的具体机制包括IL-6的来源，IL-6诱导的致病部位 影响Paneth细胞的特定信号通路以及Paneth的后续后果 细胞微扰仍未被完全理解。解决这一知识差距对于恢复IL-6至关重要 调制，一个潜在的干预机会，以防止FEMI诱导的病理。这样做的目的是 建议描述Femi减少Paneth细胞和增加易感性的关键机制 子代的肠道损伤。我们的中心假设是胎儿从母体或胎盘中接触到IL-6 (或两者)来源是Femi改变信号转导和转录激活因子-1的关键机制 在后代中的信号，导致干扰素lambda信号通路增加，降低Paneth细胞密度， 并增加了受伤的易感性。承接这项工程的理由是为了获得机械化的进展 了解女婴是如何导致新生儿发病率和死亡率的。这些知识对于发展将是至关重要的 新的预防策略，以防止早产儿的并发症和死亡率，并直接改善 早产儿的生活质量。我们的假设将通过两个目的得到验证：1)确定 IL-6及其下游信号通路在FEMI后的病理作用，以及2)决定 Femi对潘氏细胞动态平衡关键通路的影响。这项拟议的研究具有重要意义 创新，因为我们建议的研究将直接解决有关新生儿增加的知识差距 FEMI后的发病率和死亡率，特别是使用新的体内、体外、 以及研究Femi诱导的IL-6对胎儿结局的作用的体外方法。这一知识将会 导致开发有针对性的治疗方法来改善肠道健康。

Chorioamnionitis complicates up to 70% of preterm births, and is characterized by acute inflammation of the placental/fetal unit, exposing the fetus to significant inflammation. These infants have an increased risk of short- and long-term morbidities involving multiple organ systems including the intestine. However, mechanisms by which fetal exposure to maternal inflammation (FEMI) leads to adverse outcomes remain unclear. Our preliminary and published data show that an interleukin-6 (IL-6)-dependent loss of Paneth cells contributes to FEMI-associated susceptibility to bowel injury. Our data suggest that FEMI leads to: IL-6- dependent Paneth cell loss; lingering elevation of serum baseline levels of inflammatory cytokines, including IL-6; clinically relevant intestinal injury; and increased susceptibility to secondary intestinal injury. However, specific mechanisms underlying these effects including the source of IL-6, the site of IL-6-induced pathogenic action, specific signal pathways by which Paneth cells are impacted, and subsequent consequences of Paneth cell perturbation remain incompletely understood. Addressing this gap in knowledge is critical for restoring IL-6 modulation, a potential interventional opportunity for preventing FEMI-induced pathology. The objective of this proposal is to delineate key mechanisms by which FEMI decreases Paneth cells and increases susceptibility to intestinal injury in the offspring. Our central hypothesis is that fetal exposure to IL-6 from maternal or placental (or both) sources is a key mechanism by which FEMI alters signal transducers and activators of transcription-1 signaling in the offspring, leading to increased interferon lambda signal pathways, reduced Paneth cell density, and increased injury susceptibility. The rationale for undertaking this project is to gain a mechanistic advance in knowledge of how FEMI leads to neonatal morbidity and mortality. Such knowledge will be critical to develop novel preventative strategies, to prevent complications and mortality of prematurity, and to directly improve the quality of life of pre-term infants. Our hypothesis will be tested through two aims: 1) Identify the site(s) of pathologic action of IL-6 and downstream signaling pathways activated following FEMI, and 2) Determine the effects of FEMI on pathways critical to Paneth cell homeostasis. The proposed research is significant and innovative as our proposed studies will directly address the gap in knowledge regarding increased neonatal morbidity and mortality following FEMI and specifically the impact on Paneth cells using novel in vivo, in vitro, and ex vivo approaches to investigate the role of FEMI-induced IL-6 on fetal outcomes. This knowledge will lead to development of targeted therapies to improve intestinal health.