# Overcoming barriers to F508del CFTR correction

> **NIH NIH K08** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $168,264

## Abstract

PROJECT SUMMARY
 Cystic fibrosis (CF) is one of the most common fatal pediatric respiratory diseases, affecting approximately
1 in 3500 children. The development of CFTR modulators has spawned a new era of hope for CF therapeutics.
However, addressing the common F508del CFTR mutation has been challenging and CFTR modulator therapy
for this mutation is only minimally effective. An improved understanding of F508del CFTR and its correction is
the most critical therapeutic pursuit for CF patients.
 I have recently shown that the cystic fibrosis genetic modifier TGF-β diminishes CFTR function, reduces
CFTR synthesis, and impedes F508del correction. I have also reported that TGF-β is significantly increased in
CF lungs and mediates its effects by microRNA-based signaling. Specifically, I have found that the microRNA
145 (miR-145) mediates TGF-β inhibition of CFTR expression and function, and also limits F508del correction
by CFTR modulators. Discovery of this important underlying mechanism has stimulated me to expand my
career goals to microRNA therapeutics. My central hypothesis is that miR-145 antagonism interrupts TGF-β
suppression of CFTR synthesis and function in airway epithelia, representing an attractive therapeutic target.
With K08 support, I will receive training to 1) investigate mechanisms of miRNA regulation of CFTR 2) deliver
miRNA antagonists in vivo and 3) learn methods to quantify F508del therapeutic response in CF animal
models. These training goals will help advance my career focus on microRNA therapy and will be achieved
through the following Specific Aims:
Specific Aim 1: Determine the in vitro mechanism of miR-145 inhibition of CFTR in airway epithelia.
Specific Aim 2: Establish in vivo relevance of miR-145 manipulation to improve CFTR function.
Specific Aim 3: Augment CFTR correction with miR-145 antagonists in preclinical CF animal models.
 My training will be mentored by Dr. Steven Rowe (Director of the UAB Cystic Fibrosis Research Center and
expert in CF translational science) and a panel of senior investigators in a fertile research environment with
exceptional resources. Data obtained during the study period will establish the role of miR-145 inhibition to
stabilize F508del modulation and introduce miRNA antagonists as a useful adjunct to CFTR directed
therapeutics. Training provided by the K08 mechanism will facilitate my transition to research independence,
creating a niche to investigate consequence of miRNA dysregulation in CF lungs and benefit of miR-145
antagonists to improve current and next generation F508del CFTR correction. These studies will establish a
foundation for my career in CF translational science evaluating mechanisms of disease progression and
therapeutic development.

## Key facts

- **NIH application ID:** 9837477
- **Project number:** 5K08HL140190-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** William Thomas Harris
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,264
- **Award type:** 5
- **Project period:** 2017-12-24 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837477

## Citation

> US National Institutes of Health, RePORTER application 9837477, Overcoming barriers to F508del CFTR correction (5K08HL140190-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837477. Licensed CC0.

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