# CEBPD-Mediated Mechanisms of Glucocorticoid Insensitivity in Severe Asthma

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $632,844

## Abstract

PROJECT SUMMARY
Asthma is an episodic inflammatory disease that affects over 25 million Americans and manifests as airway
hyperresponsiveness to specific environmental stimuli. Despite effective medications that control asthma in
most individuals, 15% respond inadequately and suffer life-threatening exacerbations. A feature shared by
most patients with severe disease is glucocorticoid insensitivity, a poorly understood physiological process.
The airway smooth muscle (ASM), which plays an important role in asthma, is a target of glucocorticoids that
act in part via modulation of gene transcription, alteration of histone post-translational modifications, and
inhibition of transcription factors. CCAAT/Enhancer Binding Protein D (CEBPD) is a pleiotropic glucocorticoid-
responsive transcription factor that regulates inflammatory responses, cell differentiation and tissue
remodeling. Based on our data showing that CEBPD expression is (1) lower in fatal asthma vs. non-asthma
ASM, (2) induced with glucocorticoid treatment in non-asthma ASM but unchanged in fatal asthma ASM, and
that (3) decreasing CEBPD via knockdown resulted in increased IL1β-induced NFkB-luciferase expression with
glucocorticoid stimulation, our central hypothesis states that low CEBPD levels in ASM elicits transcriptomic
and epigenetic modifications that decrease glucocorticoid sensitivity. We will test this hypothesis by using the
following unbiased and complementary `omic approaches to study the effect of CEBPD on glucocorticoid
response in ASM from fatal asthma and non-asthma donors: (1) RNA-Seq to identify transcriptomic effects, (2)
proteomics to determine global histone post-translational modification effects, and (3) ChIP-Seq to measure
transcription factor binding of NFkB and the glucocorticoid receptor. An integrated analysis of RNA-Seq,
proteomics and ChIP-Seq results will identify major targets of CEBPD that influence glucocorticoid response,
whose role will be confirmed via NFkB-luciferase assays. Our project will offer insights into transcriptional and
epigenetic signatures that are characteristic of severe asthma, enable glucocorticoid sensitivity biomarker
development, and offer therapeutic insights that benefit the most vulnerable individuals with asthma.

## Key facts

- **NIH application ID:** 10130385
- **Project number:** 5R01HL133433-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Blanca E Himes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $632,844
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130385

## Citation

> US National Institutes of Health, RePORTER application 10130385, CEBPD-Mediated Mechanisms of Glucocorticoid Insensitivity in Severe Asthma (5R01HL133433-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130385. Licensed CC0.

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