Transcriptional Profiling of the Nasal Epithelium in Cystic Fibrosis

Project: Research project

Project Details


Cystic fibrosis (CF), the most common lethal autosomal-recessive disease in the United States (1/3500 newborns), is caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes the CFTR protein, an anion channel expressed in secretory epithelial cells including the airway epithelium. Around 90% of patients with CF have an in-frame deletion of a triplet encoding phenylalanine at position 508 (F508del) on at least one chromosome, leading to ineffective protein folding and trafficking. More than 2000 CFTR sequence variations have been reported, and many of these disease causing genotypes have been classified by their effect on the CFTR synthesis, trafficking, or function [1].
Pulmonary disease is the main cause of morbidity and mortality in CF. Although CF is a monogenetic disease, the correlation between a CFTR genotype and severity of pulmonary disease is poor [2]. The R117H mutation in particular has a wide range of disease expression [3]. Mechanisms for the disparity between genotype and phenotype are poorly understood. Modifier genes, environmental factors and epigenetic changes are likely contributors to the disease severity. Previous studies suggest a substantial role for additional genetic influences, known as “CF modifiers” [4-6]. Polymorphisms in a handful of genes have been associated with the genotype-phenotype discrepancy, including mannose-binding lectin 2 (MBL2) and transforming growth factor beta 1 (TGFβ1). [7, 8] It is anticipated that there are other CF modifying genes that remain to be discovered, as well as contributions from environment and epigenetics changes [9]. It is likely that the impact of these influences may be reflected in gene expression analysis.
Two small molecular modulators of the mutant CFTR channel have been approved by the FDA, and have been determined to improve protein folding and trafficking (VX809, or lumacaftor) or restore CFTR channel current (VX770, or ivacaftor), and are available as ivacaftor alone, or as a combination drug. Interestingly, it has also been observed that despite the same genotype, patients have heterogeneous responses to these modulators which is unexplained [10, 11]. We hypothesize that the observed heterogeneity in clinical response may also be reflected in a heterogeneous response in gene expression.
The examination of gene expression can now be accomplished with thousands of genes simultaneously using high-throughput RNA sequencing (RNA-Seq), a technology developed in 2008 for comprehensive transcriptome study [12]. Compared to the traditional method of measuring differential gene expression, gene microarrays, RNA-Seq is an unbiased approach which can detect all mRNA transcripts, operates at higher resolution, and has a wider dynamic range. Meanwhile, there is growing interest in using nasal epithelial cells as a surrogate for studying and diagnosing pulmonary diseases, being a much less invasive sampling process than bronchoscopy or lung biopsy. While CFTR is expressed in nasopharyngeal epithelial cells as well as bronchial epithelial cells, and several groups of investigators have already determined that nasal epithelial tissue serves as a reasonable surrogate for the transcriptome of the lower airway epithelium in other diseases [13], there is no direct evidence for this in CF. We therefore propose two interrelated, but independent, Aims:

Specific Aim 1: Investigate the variability in genotype-phenotype correlation in CF using nasal epithelial transcriptomic profiling. In this Aim, we will investigate i
Effective start/end date4/1/183/31/21


  • Cystic Fibrosis Foundation (SALA18I0)


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