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

肝 IkBb 介导的持续 NFkB 激活在新生儿肺损伤和异常发育中的作用

• 批准号: 9258241
• 负责人: Clyde Jason Wright
• 金额: $ 37.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258241
• 关键词: Adult; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Binding; Biological Markers; Bronchopulmonary Dysplasia; Cell Nucleus; Cells; Chronic; Data; Development; Dimerization; Endotoxemia; Equilibrium; Family; Foundations; Gene Expression; Gene Targeting; Genetic; Hepatic; I Kappa B-Alpha; Immune signaling; Immunologics; Impairment; Incidence; Infant; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Innate Immune System; Kinetics; Laboratories; Life; Link; Lipids; Liver; Lung; Mediating; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Natural Immunity; Neonatal; Nuclear; Nuclear Translocation; Organ; Outcome; Pathogenesis; Pattern; Perinatal; Pharmacology; Phosphorylation; Physiological; Plasmids; Play; Premature Birth; Premature Infant; Prevention approach; Protein Isoforms; Proteins; Pulmonary Inflammation; Risk; Role; Signal Transduction; Small Interfering RNA; Stimulus; Stress; Testing; Therapeutic; Transcription Repressor/Corepressor; Work; base; dimer; in vivo; lung development; lung injury; macrophage; nanoparticle; neonatal care; neonatal lung injury; neonate; prevent; pulmonary function; response; transcription factor; transcriptome; upstream kinase

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.

项目摘要 支气管肺发育不良（BPD）是最常见的发病率，早产并预测 肺部和神经发育结果不良。尽管有充分记录的关联 炎症和BPD，目前没有安全有效的抗炎疗法可预防BPD 可用的。新生儿先天免疫反应如何有助于BPD的发病机理，未知， 限制治疗选择。我们的总体目的是确定连接的分子机制 新生儿先天免疫响应和肺发育受损，有助于 BPD。重要的是，我的实验室的最新研究确定 转录因子NFκB的关键抑制蛋白的表达模式。由于NFκB起着核心作用 在调节先天免疫时，这些发现使我们提出了一个新的组织假设，将 新生儿肝率了免疫响应肺部损伤。我们假设肝表达 NFκB抑制蛋白的IκB家族的概况导致持续的促炎先天性免疫 对系统性炎症应激的反应，导致持续的肺部感染，损伤和 发展受损。我们提出了三个特定的目的，以检验这一假设并确定免疫学 发育中的肺和肝脏之间的串扰。在AIM 1中，我们将测试细胞内平衡是否 IκBα/IκBβ决定了炎症诱导的NFκB的幅度，持续时间和选择性 转录组。在AIM 2中，我们将测试是否有强大而持续的促炎新生儿先天免疫 反应有助于肺损伤和异常发育。在AIM 3中，我们将测试是否抑制 炎性应激诱导的IκBβ介导的肝NFB信号传导可防止延长促炎基因 表达并减轻新生儿肺损伤。我们的假设代表了我们的方式的范式转变 通过连接持续的促炎新生儿先天免疫反应来预防BPD 由肝IκBβ/NFκB信号传导介导的肺损伤和随后的异常发育。这些研究 将为旨在将IκBβ /NFκB信号靶向药物的转化工作提供基础 防止在处于危险的婴儿中BPD。