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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $490,696

## Abstract

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.

## Key facts

- **NIH application ID:** 9837467
- **Project number:** 5R01HL132941-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Clyde Jason Wright
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,696
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837467

## Citation

> US National Institutes of Health, RePORTER application 9837467, Role of hepatic IkBb-mediated sustained NFkB activation in neonatal lung injury and abnormal development (5R01HL132941-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837467. Licensed CC0.

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