# Airway Inflammatory Pathways Regulating Glucocorticoid Receptor Phosphorylation

> **NIH NIH R01** · LONG ISLAND UNIVERSITY C. W. POST CENTER · 2021 · $92,716

## Abstract

PROJECT SUMMARY
Increased airway smooth muscle (ASM) mass, a major feature of airway remodeling in asthma,
profoundly contributes to asthma morbidity, mortality, and pathogenesis. This increased mass is due in
large part to enhanced proliferative activity of ASM cells. Unfortunately, proliferation of these latter cells is
unaffected by current asthma medications, as the process appears to be insensitive to glucocorticoid (GC)
effects. While research aimed at understanding the basis of GC insensitivity (GCI) has focused on the role of
immune cells, few investigators have studied GCI in ASM cells, the pivotal cell regulating bronchomotor tone.
The long-term goal of this research is to identify factors that impair the sensitivity of the ASM proliferative
response to GC in patients with asthma, with the ultimately goal of establishing therapeutic strategies to
circumvent GCI. The current proposal will examine the cellular and molecular mechanisms by which growth
factors (GFs) modulate ASM sensitivity to GCs. Using unique cellular models of ASM cells derived from patients
with asthma, our exciting preliminary data supports the central hypothesis that GF-induced abnormal site-specific
phosphorylation of glucocorticoid receptor (GR) impairs ASM sensitivity to GC. These data now suggest that
(previously unappreciated) GR phosphorylation at serine 134 (ser134) residue inhibits GR signaling. These data
also suggest that GF-induced activation of serine/threonine kinase protein kinase B (PKB/Akt) and
serine/threonine protein phosphatase 2A (PP2A) regulates GR-ser134 phosphorylation. The rationale for the
proposed research is that understanding the interplay among GR signaling and GF-induced kinases and/or
phosphatases may uncover critical information for the development of novel therapeutics to overcome GCI in
asthma. Our hypotheses will be tested by pursuing four specific aims: to identify the functional consequences of
GF-induced abnormal GR site-specific phosphorylation on GR signaling (Aim 1); to characterize the contribution
of kinases and phosphatases to GF-induced abnormal GR site-specific phosphorylation (Aim 2); and to elucidate
the role of steroid-target genes in modulating GC anti-proliferative effects in ASM cells (Aim 3). To this end, we
generated tools (antibody, mutated constructs) to examine the role of GR-ser134 phosphorylation. In all aims,
pharmacological inhibitors, mutated constructs, siRNA, and expression vectors will be used to modulate the
expression of steroid co-repressor, kinases, phosphatases, and steroid-target genes, after which GR site-specific
phosphorylation, GR-mediated transactivation activities and sub-cellular localization, and ASM growth will be
analyzed using state-of-the-art approaches already established in our laboratories. We will also determine the
clinical significance of our in vitro observations by examining whether the aforementioned pathways are activated
in tissues using endobronchial biopsies from subjects b...

## Key facts

- **NIH application ID:** 10159949
- **Project number:** 5R01HL111541-11
- **Recipient organization:** LONG ISLAND UNIVERSITY C. W. POST CENTER
- **Principal Investigator:** OMAR TLIBA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $92,716
- **Award type:** 5
- **Project period:** 2018-12-01 → 2022-03-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159949

## Citation

> US National Institutes of Health, RePORTER application 10159949, Airway Inflammatory Pathways Regulating Glucocorticoid Receptor Phosphorylation (5R01HL111541-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159949. Licensed CC0.

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