Role of hepatic IkBb-mediated sustained NFkB activation in neonatal lung injury and abnormal development

项目总结 支气管肺发育不良(Bpd)是早产最常见的并发症。 肺部和神经发育不良。尽管有很好的证据表明 炎症和BPD，目前还没有安全有效的抗炎疗法来预防BPD。 可用。新生儿先天免疫反应在BPD发病机制中的作用尚不清楚。 限制了治疗选择。我们的首要目标是确定连接 新生儿先天免疫反应和肺发育受损参与了慢性阻塞性肺疾病的发病 每桶。重要的是，我的实验室最近的研究发现了一种发育调节的、肝脏特异的 转录因子核因子κB关键抑制蛋白的表达模式作为核因子κB发挥核心作用 在调节先天免疫方面，这些发现使我们提出了一种新的组织假说，将 新生儿肝脏对肺损伤的先天免疫反应。我们假设肝脏的表达 IκB家族核因子κB抑制蛋白的特征导致持续的促炎先天免疫 对全身性炎症应激的反应，导致持续的肺部炎症、损伤和 发育受阻。我们提出了三个具体目标来检验这一假设并确定免疫学 发育中的肺和肝之间的串音。在目标1中，我们将测试细胞内平衡是否 IκBα/IκBβ决定炎症应激诱导的核因子κB的大小、持续时间和选择性 转录组。在目标2中，我们将测试强健和持续的促炎性新生儿先天免疫 反应导致肺损伤和发育异常。在目标3中，我们将测试抑制 炎症应激诱导，IκBβ介导的肝组织核因子B信号阻止延长的促炎基因 表达并减轻新生儿肺损伤。我们的假设代表了一种范式的转变 通过联系持续的促炎性新生儿先天免疫反应来预防BPD 肝脏IκBβ/NFκB信号转导肺损伤及随后的异常发育。这些研究 将为药物靶向IκBβ/NFκB信号转导的翻译工作提供基础 预防高危婴儿的BPD。

PROJECT SUMMARY Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and predicts poor pulmonary and neurodevelopmental outcomes. Despite the well-documented association between inflammation and BPD, no safe and effective anti-inflammatory therapies to prevent BPD are currently available. How the neonatal innate immune response contributes to the pathogenesis of BPD is unknown, limiting therapeutic options. Our overarching aim is to determine the molecular mechanisms linking the neonatal innate immune response and impaired lung development that contributes to the pathogenesis of BPD. Importantly, recent studies in my laboratory identified a developmentally-regulated, hepatic-specific pattern of expression for key inhibitory proteins of the transcription factor NFκB. As NFκB plays a central role in regulating innate immunity, these findings have led us to propose a new organizing hypothesis linking the neonatal hepatic innate immune response to pulmonary injury. We hypothesize that the hepatic expression profile of the IκB family of NFκB inhibitory proteins results in a sustained pro-inflammatory innate immune response to systemic inflammatory stress that contributes to ongoing pulmonary inflammation, injury and impaired development. We propose three specific aims to test this hypothesis and determine the immunologic cross-talk between the developing lung and liver. In Aim 1, we will test whether the intracellular balance of IκBα/IκBβ dictates the magnitude, duration and selectivity of the inflammatory-stress induced NFκB transcriptome. In Aim 2, we will test whether a robust and sustained pro-inflammatory neonatal innate immune response contributes to lung injury and abnormal development. In Aim 3, we will test whether inhibiting inflammatory stress-induced, IκBβ-mediated hepatic NFB signaling prevents prolonged pro-inflammatory gene expression and attenuates neonatal lung injury. Our hypothesis represents a paradigm shift in how we approach the prevention of BPD by linking a sustained pro-inflammatory neonatal innate immune response mediated by hepatic IκBβ/NFκB signaling to lung injury and subsequent abnormal development. These studies will provide the foundation for translational work aimed at pharmacologically targeting IκBβ /NFκB signaling to prevent BPD in at-risk infants.