# Nasal lavage exosome analysis specifies therapeutic targets for precision treatment in cystic fibrosis

> **NIH NIH P20** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $229,500

## Abstract

ABSTRACT 
Cystic Fibrosis (CF) is a Mendelian recessive “monogenic” disorder caused by mutations in CFTR, with a 
broad range of lung disease severity. Heritability studies show that genetic variation (“modifier genes”), rather 
than allelic variation in CFTR, is responsible for most of the variability in CF lung disease severity (heritability 
estimate = 0.54). In 134 CF patients with genomic SNP data, we performed respiratory (nasal) epithelial 
transcriptomic mRNA studies to determine modifier genes. This analysis identified heritable differential 
expression of genes in pathways pertinent to the pathophysiology of CF lung disease, highlighting that 
dysregulated inflammation is detrimental in CF. However, the mechanism of pathogenesis for these candidate 
modifier genes remains incompletely understood. miRNA regulation is one undefined mechanism of effect for 
modifier genes on CF lung disease, and we have now isolated miRNAs from secreted extracellular vesicles 
(EVs) in readily accessible CF nasal lavage. Building on candidate gene modifiers identified in our 
transcriptomic studies, we will test the hypothesis that extracellular vesicle (EV) miRNAs are modifiers of 
inflammatory signaling that contribute to the severity and progression of CF lung disease. We will take a global 
approach to characterize differential expression of EV miRNAs in CF respiratory secretions, as well as query the 
mechanistic role of specific candidate EV miRNAs on CF airway disease in vitro. In Aim 1 we will perform 
miRNASeq on already obtained nasal lavage biospecimens from 134 CF patients, and identify miRNAs 
associated with CF lung disease severity. We will determine the effects of these identified miRNAs on gene 
regulation, using our existing intra-subject nasal mucosal RNAseq data, plus validate candidate miRNAs in an 
independent CF cohort. In our transcriptomic studies, we have already shown that increased expression of 
genes in the methionine salvage pathway (also implicated in CF GWAS) is associated with worse CF lung 
disease. However, the mechanism of influence for this pathway in the pathogenesis of CF remains unknown, 
presenting the importance of mechanistic validation studies. We show that the key substrate of this pathway, 
methylthioadenosine (MTA), reduces levels of a top-ranked candidate miRNA-21 (identified by our in silico 
analysis), in THP-1 macrophage secreted extracellular vesicles (EV). Importantly, miRNA-21 is known to 
stimulate inflammatory signaling. In Aim 2, we will test the hypothesis that MTA treatment decreases secreted 
EV miRNA-21 levels and results in reduced inflammatory cytokine production directly in macrophages, which 
are critical to CF inflammation. We will further test the effect of these secreted EVs, and the direct effects of 
reduced miRNA-21, on attenuating the inflammatory response to LPS in human CF airway epithelial cells 
(AECs) cultured at air-liquid interface. Our proposed studies will elucidate candidate...

## Key facts

- **NIH application ID:** 9869924
- **Project number:** 5P20GM130423-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Deepika Polineni
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,500
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869924

## Citation

> US National Institutes of Health, RePORTER application 9869924, Nasal lavage exosome analysis specifies therapeutic targets for precision treatment in cystic fibrosis (5P20GM130423-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9869924. Licensed CC0.

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