Posttranscriptional Regulation of Inflammatory Molecules in Cystic Fibrosis
Abstract
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in a chloride ion channel called cystic fibrosis transmembrane conductance regulator (CFTR). CF patients frequently develop chronic lung inflammation and refractory respiratory infection, most commonly by Pseudomonas aeruginosa (P. aeruginosa, PA). The CF lung disease is one of the major causes of the morbidity and mortality in CF patients, and development of anti-inflammatory therapeutics for CF is a major goal. Inflammatory molecules are regulated through posttranscriptional mechanisms by microRNAs (miRNAs) and mRNA-binding proteins. miRNAs are endogenous non-coding RNA molecules that have been found to regulate various cellular processes by destabilizing target mRNAs. Recent studies indicate that microRNAs are key molecules in disease development and therapy. Additionally, several RNA-binding proteins (RBP) have been shown to coordinate with miRNAs and regulate expression of inflammatory genes. A class of RBPs recognize and bind to adenosine-uridine rich regions (ARE regions) in the 3 UTRs of mRNAs and are known as ARE-binding proteins (AUBPs). However, the role of these factors in the regulation of the inflammation in CF has not been well studied. Therefore, my overall research theme is to determine posttranscriptional regulation of inflammatory molecules in CF. Based on previous findings from our laboratory, my thesis especially focuses on the mechanisms of posttranscriptional regulation of IL-8 expression in CF by miR-155 and HuR. Our findings indicated that inflammatory mediators and Pseudomonas infection modulate IL-8 and as well as miR-155 expression in CF lung epithelial cell. To further investigate mechanisms of posttranscriptional regulation of IL-8 mRNA, we subsequently searched for proteins and miRNAs which bind to the ARE region of IL-8 mRNA specifically in CF. Our data show that HuR and miR-16 bind to the ARE region, and regulate IL-8 mRNA stability. Additionally we examined
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 10, 2015
- Accession Number
- AD1127928
Entities
People
- Motohiro Tsuchiya
Organizations
- Uniformed Services University of the Health Sciences