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Principal Investigator: Clyde Jason Wright
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2021
Award: $490,696
Funding agency: National Heart Lung and Blood Institute
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 NFB 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.
Terms: <21+ years old><Adult><Adult Human><Affect><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Approaches to prevention><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Binding><Biological Markers><Bronchopulmonary Dysplasia><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Chronic><Data><Development><Endotoxemia><Equilibrium><Family><Foundations><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Hepatic><I Kappa B A><I Kappa B-Alpha><I kappa B-alpha protein><IKB-Alpha><IKappaB><IKappaB-Alpha><IKappaB/MAD-3><IkappaBalpha><Immune signaling><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impairment><Incidence><Infant><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Injury><Innate Immune Response><Innate Immune System><Innate Immunity><Intracellular Communication and Signaling><Isoforms><IκBα><Kinetics><Laboratories><Life><Link><Liver><Lung><Lung Respiratory System><Lung damage><MAD-3 protein><MAD3><MAD3 inhibitor><Major Histocompatibility Complex Enhancer-Binding Protein MAD3><Mediating><Mice><Mice Mammals><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Mφ><NF-Kappa B Inhibitor Alpha><NF-kappaB inhibitor alpha><Native Immunity><Natural Immunity><Neonatal><Non-Specific Immunity><Nonspecific Immunity><Nuclear><Nuclear Factor Kappa-B Inhibitor><Nuclear Factor of Kappa Light Chain Gene Enhancer in B Cells Inhibitor><Nuclear Factor of Kappa Light Chain Gene Enhancer in B Cells Inhibitor, Alpha><Nuclear Translocation><Nucleus><Organ><Outcome><Pathogenesis><Pattern><Perinatal><Peripartum><Pharmacology><Phosphorylation><Physiologic><Physiological><Plasmids><Play><Pneumonitis><Premature Birth><Prematurely delivering><Preterm Birth><Prevention approach><Protein Isoforms><Protein Phosphorylation><Proteins><Pulmonary Inflammation><Risk><Role><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Stimulus><Stress><Testing><Therapeutic><Transcription Factor Proto-Oncogene><Transcription Repressor><Transcription factor genes><Transcriptional Repressor><Work><adulthood><antiinflammatory><balance><balance function><base><bio-markers><biologic marker><biological signal transduction><biomarker><chronic lung disease in infants><chronic lung disease in neonatal infants><chronic lung disease in neonates><chronic lung disease in newborns><chronic lung disease in prematurity><developmental><dimer><genetic repressor><global gene expression><global transcription profile><hepatic body system><hepatic organ system><in vivo><infant chronic lung disease><inflammatory mediator><injuries><lipid nanoparticle><lung development><lung function><lung injury><macrophage><neonatal care><neonatal chronic lung disease><neonatal lung injury><neonate><newborn chronic lung disease><premature childbirth><premature delivery><premature neonates><premature newborn><preterm delivery><preterm neonate><preterm newborn><prevent><preventing><pulmonary><pulmonary function><response><siRNA><social role><transcription factor><transcriptome><upstream kinase>