# Correcting Pathogenic TGF beta Activity in the Airway

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $446,565

## Abstract

ABSTRACT
Homeostasis of the airway surface liquid (ASL) in lung is critically dependent on chloride ion (Cl-) transport,
mediated by the apical channel, CFTR (cystic fibrosis transmembrane conductance regulator). CFTR gene
mutations associated with the most common autosomal recessive disease in Caucasians, cystic fibrosis (CF)
result in loss of CFTR function and severe impairment of the ASL volume regulation. Deletion of F508
(F508del) in the CFTR gene is present in 90% of CF patients; it blocks CFTR biosynthetic processing, reduces
CFTR Cl- channel function, and decreases CFTR mRNA stability and translation. It is estimated that the classic
severe CF phenotype develops when the CFTR channel function is less than 1% of normal and at least 10%
function is needed to alleviate the severe phenotype. Therapies targeting the basic molecular defects in CF
demonstrate potential but are insufficient for most patients. While the FDA-approved drug VX-770 potentiates
CFTR channel “open” probabilities and improves lung function for less than 10% of patients with the rare
mutation G551D, the combined use of VX-770 and a corrector VX-809 that rescues the folding and processing
defect was only marginally effective for F508del patients. CF patients with more severe lung disease were
entirely resistant to such therapy. Transforming growth factor (TGF)-β1 contributes to resistance of corrector
therapy by blocking CFTR translation and represses ancillary ion channels critical to residual ASL homeostasis
in CF, namely BK (a Ca+2-activated K+ channel) and ANO1 (a Ca+2-activated Cl- channel). High TGF-β1 levels
are seen in 40% of F508del homozygous patients due to polymorphisms in the TGF-β1 gene. Air pollutants,
including cigarette smoke also increase TGF-β1 levels. The concomitant upregulation of TGF-β1 in turn
increases the severity of CF lung disease in F508del homozygous patients and presents a major block to
therapies aimed at F508del-CFTR rescue. We propose that targeting the pathogenic TGF-β1 activity would
improve the residual ASL volume homeostasis in CF by restoring the function of BK and ANO1 channels. It
would also increase the efficacy of therapy for F508del CF patients by restoring the diminished 508del-CFTR
translation and allowing increased activity of the mutant CFTR channel function. Thus, defining TGF-β1
mediators in lung tissue presents an opportunity to design novel drugs eliminating the pathogenic TGF-β1
activity in CF patients. Our central hypothesis is that the targeted reduction of TGF-β1 activity will ameliorate
negative effects on CFTR, BK, and ANO1 channels and ASL homeostasis, and provide a novel approach to
treat F508del CF patients. Our specific aims are to test the hypothesis: (1) that Dab2 is a TGF-β1 adaptor that
inhibits the residual ASL homeostasis in CF bronchial epithelium by directing nuclear transport of Smad3 to
repress the ancillary channels, BK and ANO1; (2) that the Dab2-Smad3 interactions upregulates microRNAs
that repress ...

## Key facts

- **NIH application ID:** 10189898
- **Project number:** 7R01HL144539-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Agnieszka Swiatecka-Urban
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $446,565
- **Award type:** 7
- **Project period:** 2019-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189898

## Citation

> US National Institutes of Health, RePORTER application 10189898, Correcting Pathogenic TGF beta Activity in the Airway (7R01HL144539-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189898. Licensed CC0.

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