# The epithelial NFkB-BRD4 pathway in airway inflammation and remodeling

> **NIH NIH P01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $459,464

## Abstract

Severe lower respiratory tract infections (LRTIs) are associated with long-term reductions in pulmonary
function, a highly significant indicator of chronic lung disease in adults. Work in our current funding period has
elucidated the central role of the epigenetic coactivator bromodomain-containing protein 4 (BRD4) complexed
with NFκB/RelA in mucosal inflammatory responses. Not only does the RelA•BRD4 complex activate
inflammation, but it also activates the TGFβ-mediated fibrotic program. We have demonstrated that small-
molecule inhibition of BRD4 HAT prevents inflammation, fibrosis, and remodeling in mouse models of repetitive
viral and allergen challenges. These findings provide the unifying mechanism linking the innate RelA·BRD4
complex with inflammation and airway remodeling. During the next funding period, we will test the
hypothesis that the BRD4 histone acetyl transferase (HAT)-chromatin remodeling complex (CRC) is an
epigenetic regulator that acutely activates the innate immune response and chronically activates
airway remodeling. We will pursue three hypotheses that: 1) The NFκB/RelA-activated BRD4 HAT- CRC
links RSV infection with the remodeling program. We will examine the role of RelA in activation and
redistribution of the BRD4 HAT-CRC in fibrotic gene programs in primary human small airway epithelial cells
(hSAECs) depleted of BRD4, complemented with BRD4 HAT mutations using air-liquid interface (ALI) cultures
established by the Infant Bronchiolitis and Viral Core (IBVC). We will test the functional consequences of our
original observations that BRD4 is in a dynamic complex with the SWI/SNF-related, Matrix-associated, Actin-
dependent Regulator of Chromatin (SMARC) CRC in inflammation/remodeling. 2) RelA activates the
epithelial BRD4 pathway to mediate RSV-induced disease and remodeling. We will use a novel RelA
mouse knockout model to test the selective role of RelA signaling by tracheo-bronchiolar cells in RSV-induced
inflammation and remodeling in vivo. We will test the effect of BRD4 silencing using BRD4CKO and a novel
specific BRD4 inhibitor. We will measure TGFβ fibrotic markers in nasopharyngeal samples from children with
LRTI vs uncomplicated URI and normals. 3) RSV proteins restructure the RelA•BRD4 HAT-CRC complex
to “prime” allergic airway remodeling. In this aim, we will determine the functional consequences of our
findings that RSV proteins interact with the RelA•BRD4 complex, and we will conduct experiments elucidating
how RSV infection reprograms the RelA•BRD4 HAT-CRC to enhance (“prime”) allergen-induced myofibroblast
expansion and airway remodeling. Our project is synergistic with the studies in RP2 to examine the role of
RelA in the regulation of antioxidant genes/NRF2, and with RP3 to examine the role of 8-oxoguanine DNA
glycosylase (OGG1) in RelA-activated remodeling. Our results will identify the BRD4 HAT-CRC as an
important target in inflammation-remodeling, and they will provide proof-of-principle to advance ...

## Key facts

- **NIH application ID:** 9974468
- **Project number:** 5P01AI062885-13
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Allan R. Brasier
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,464
- **Award type:** 5
- **Project period:** 2004-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974468

## Citation

> US National Institutes of Health, RePORTER application 9974468, The epithelial NFkB-BRD4 pathway in airway inflammation and remodeling (5P01AI062885-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974468. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*