# The molecular and cellular mechanisms of the STAT3 mutation-mediated pulmonary disorder in Autosomal Dominant Hyper IgE Syndrome (AD-HIES)

> **NIH NIH U01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $748,549

## Abstract

Abstract: Autosomal Dominant Hyper IgE Syndrome (AD-HIES) is a rare genetic disease characterized by
elevated IgE, eosinophilia, eczema, recurrent skin infections, and pneumonia. AD-HIES is most frequently
caused by mutations in the STAT3 gene, leading to impaired TH17 cell differentiation and recurrent pulmonary
infections, a major cause of morbidity and mortality in AD-HIES patients. Airway mucus obtained from AD-
HIES patients is abnormally thick (hyperconcentrated), viscous, and adherent. The abnormal mucus properties
are associated with chronic inflammation and mucus obstruction, resembling features observed in cystic
fibrosis (CF) and primary ciliary dyskinesia (PCD). In CF and PCD, loss of the CFTR or motile cilia,
respectively, leads to hyperconcentrated mucus, impaired mucociliary clearance (MCC), and chronic infection,
suggesting candidate pathways for the pathogenesis of AD-HIES lung disease. Our preliminary in vitro and in
vivo studies suggest both pathways are defective in AD-HIES: (1) CFTR transcription and function are
downregulated; and (2) expression of ciliary shaft dyneins are also downregulated. These data led us to test
the hypothesis that defective STAT3 perturbs mucus clearance in AD-HIES lungs. Three Aims are
prepared to test this hypothesis. Specific Aim 1: STAT3 regulates CFTR-mediated airway surface
hydration and mucus concentration. We will measure nasal PD, sweat chloride values in AD-HIES patients
in vivo, and CFTR activity in vitro using primary AD-HIES human bronchial epithelial (HBE) cultures at baseline
and after exposure to inflammatory stimuli. Therapeutic approaches aimed to improve CFTR expression and
function will be assessed in AD-HIES HBE cells. Specific Aim 2: STAT3 is required for ciliated cell
genesis, function, and mucociliary transport. We will image motile cilia ultrastructure in freshly collected
nasal scrapes by TEM. Ciliary beat frequency and direction, waveform patterns, regulation of ATP/adenosine
concentrations, and mucus clearance rate in the AD-HIES HBE cells will be measured. Therapies aimed to
restore MCC and mucus hydration will be assessed for their efficacy in AD-HIES HBE cells. Specific Aim 3:
AD-HIES is associated with airway mucus plugging and heterogeneous ventilation that can be
quantified using advanced CT and MRI imaging techniques. To quantify the muco-obstructive phenotype
in AD-HIES patients in vivo, we will perform quantitative imaging analyses by conventional CT, regional ultra-
high resolution CT scan, and high-performance low field MRI to measure mucus plug, airway trapping and gas
exchange distribution. This collaborative project combines the strengths of the NHLBI, NIAID, NIH Clinical
Center, Johns Hopkins CF Center and UNC’s Marsico Lung Institute, to study AD-HIES lung disease. Data
derived from this application should identify the molecular and cellular mechanism(s) of STAT3 in regulating
MCC-mediated innate host defense, optimal imaging modalities for detecting mucus ...

## Key facts

- **NIH application ID:** 10393987
- **Project number:** 1U01HL156655-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Richard Charles Boucher
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $748,549
- **Award type:** 1
- **Project period:** 2022-03-05 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393987

## Citation

> US National Institutes of Health, RePORTER application 10393987, The molecular and cellular mechanisms of the STAT3 mutation-mediated pulmonary disorder in Autosomal Dominant Hyper IgE Syndrome (AD-HIES) (1U01HL156655-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393987. Licensed CC0.

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