Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia.

Autor:	Abou Alaiwa MA; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242., Hilkin BM; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Price MP; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Gansemer ND; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Rector MR; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Stroik MR; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Powers LS; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Whitworth KM; Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211., Samuel MS; Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211., Jain A; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Ostedgaard LS; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Ernst SE; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Philibert W; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242., Boyken LD; Department of Pathology, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Moninger TO; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Karp PH; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Hornick DB; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Sinn PL; Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Fischer AJ; Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Pezzulo AA; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., McCray PB Jr; Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Meyerholz DK; Department of Pathology, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Zabner J; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242., Prather RS; Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211., Welsh MJ; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa 52242., Stoltz DA; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa 52242.; Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 21. Date of Electronic Publication: 2024 Aug 21.
DOI:	10.1101/2024.05.22.594822
Abstrakt:	Mutations in more than 50 different genes cause primary ciliary dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment. As with many other diseases, a better understanding of pathogenic mechanisms may lead to effective treatments. To pursue disease mechanisms, we used CRISPR-Cas9 to develop a PCD pig with a disrupted DNAI1 gene. PCD pig airway cilia lacked the outer dynein arm and had impaired beating. MCT was impaired under both baseline conditions and after cholinergic stimulation in PCD pigs. Neonatal PCD pigs developed neonatal respiratory distress with evidence of atelectasis, air trapping, and airway mucus obstruction. Despite airway mucus accumulation, lung bacterial counts were similar between neonatal wild-type and PCD pigs. Sinonasal disease was present in all neonatal PCD pigs. Older PCD pigs developed worsening airway mucus obstruction, inflammation, and bacterial infection. This pig model closely mimics the disease phenotype seen in people with PCD and can be used to better understand the pathophysiology of PCD airway disease. Competing Interests: The authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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