A Genomic Signature Approach to Rescue ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

Shyam Ramachandran; Samantha R Osterhaus; Philip H Karp; Michael J Welsh; Paul B McCray

doi:10.1165/rcmb.2014-0007OC

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A Genomic Signature Approach to Rescue ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

Journal article

Open access

Peer reviewed

A Genomic Signature Approach to Rescue ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

Shyam Ramachandran, Samantha R Osterhaus, Philip H Karp, Michael J Welsh and Paul B McCray

American journal of respiratory cell and molecular biology, Vol.51(3), pp.354-362

09/2014

DOI: 10.1165/rcmb.2014-0007OC

PMCID: PMC4189493

PMID: 24669817

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Abstract

The most common cystic fibrosis (CF) mutation, ΔF508, causes protein misfolding, leading to proteosomal degradation. We recently showed that expression of miR-138 enhances CF transmembrane conductance regulator (CFTR) biogenesis and partially rescues ΔF508-CFTR function in CF airway epithelia. We hypothesized that a genomic signature approach can be used to identify new bioactive small molecules affecting ΔF508-CFTR rescue. The Connectivity Map was used to identify 27 small molecules with potential to restore ΔF508-CFTR function in airway epithelia. The molecules were screened in vitro for efficacy in improving ΔF508-CFTR trafficking, maturation, and chloride current. We identified four small molecules that partially restore ΔF508-CFTR function in primary CF airway epithelia. Of these, pyridostigmine showed cooperativity with corrector compound 18 in improving ΔF508-CFTR function. There are few CF therapies based on new molecular insights. Querying the Connectivity Map with relevant genomic signatures offers a method to identify new candidates for rescuing ΔF508-CFTR function.

corrector compound 18

airway epithelia

Original Research

cystic fibrosis

Connectivity Map

small molecule compound

Details

Title: Subtitle: A Genomic Signature Approach to Rescue ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function
Creators: Shyam Ramachandran - Department of Pediatrics
Samantha R Osterhaus - Department of Pediatrics
Philip H Karp - Deparment of Internal Medicine, and
Michael J Welsh - Deparment of Internal Medicine, and
Paul B McCray - Department of Pediatrics
Resource Type: Journal article
Publication Details: American journal of respiratory cell and molecular biology, Vol.51(3), pp.354-362
DOI: 10.1165/rcmb.2014-0007OC
PMID: 24669817
PMCID: PMC4189493
NLM abbreviation: Am J Respir Cell Mol Biol
ISSN: 1044-1549
eISSN: 1535-4989
Publisher: American Thoracic Society
Language: English
Date published: 09/2014
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Neurosurgery; Internal Medicine
Record Identifier: 9984020638402771

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