权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结