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Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis

Zhichao Liu1, Jürgen Borlak2, Weida Tong1

  • 1Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 USA.

Genome Medicine
|December 9, 2014
PubMed
Abstract

Insights

Drug repurposing for cystic fibrosis (CF) identified novel therapeutic targets by constructing microRNA (miRNA) and transcription factor (TF) feed-forward loops (FFLs). This approach revealed 26 potential drug candidates for CF treatment.

Area of Science:

  • Genetics and Molecular Biology
  • Pharmacology and Drug Discovery

Background:

  • Cystic fibrosis (CF) is a genetic disorder caused by CF transmembrane conductance regulator (CFTR) gene mutations, leading to severe lung and digestive issues.
  • Current CF treatments primarily manage symptoms, highlighting the need for improved therapeutic strategies.

Purpose of the Study:

  • To explore drug repurposing for CF by investigating microRNA (miRNA) and transcription factor (TF) gene networks.
  • To identify and construct disease-specific feed-forward loops (FFLs) as potential therapeutic targets for CF.

Main Methods:

  • Conducted comprehensive database searches to identify enriched TFs and miRNAs in CF and CFTR gene networks.
  • Validated target genes and predicted miRNA targets using bioinformatics tools and STRING analysis for protein-protein interactions.
  • Established an in silico drug repurposing pipeline based on miRNA/TF regulation within CF/CFTR networks.

Main Results:

  • Constructed 15 composite FFLs in human airway epithelium, with nine validated in patient samples and CF cell lines.
  • Identified ubiquitin-mediated proteolysis and ER protein processing as key functions within the FFLs, related to protein folding, sorting, and degradation.
  • Screened 48 drug candidates, confirming 26 with existing literature or clinical trial relevance for CF treatment.

Conclusions:

  • The study successfully constructed FFLs, identifying promising drug repurposing candidates for cystic fibrosis.
  • The developed strategy offers a novel approach for CF treatment and has potential applicability to other genetic disorders.

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