Animal models of cystic fibrosis (CF) are essential for investigating disease mechanisms and trialling potential therapeutics. This study generated two CF rat models using clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) gene editing. One rat model carries the common human Phe508del (ΔF508) CF transmembrane conductance regulator (CFTR) mutation, whereas the second is a CFTR knockout model. Phenotype was characterized using a range of functional and histological assessments including nasal potential difference to measure electrophysiological function in the upper airways, RNAscope in situ hybridization and quantitative PCR to assess CFTR mRNA expression in the lungs, immunohistochemistry to localize CFTR protein in the airways, and histopathological assessments in a range of tissues. Both rat models revealed a range of CF manifestations including reduced survival, intestinal obstruction, bioelectric defects in the nasal epithelium, histopathological changes in the trachea, large intestine, and pancreas, and abnormalities in the development of the male reproductive tract. The CF rat models presented here will prove useful for longitudinal assessments of pathophysiology and therapeutics.Copyright © 2020. Published by Elsevier Inc.
The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression.
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