cystic fibrosis: using ferrets as a disease model
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Terms and Abbreviations
CF = Cystic Fibrosis SCNT = Somatic Cell Nuclear Transfer MI = Meconium Ileus LFT = Liver Function Test ALT = Alanine Aminotransferase UDCA = Ursodeoxycholic Acid FABPi = Fatty acid binding promoter
Background
CF affects: 1 in 3,500 newborns each year
People of mixed European descent
Caused by a defective CFTR gene Codes for epithelial chloride channel
Background CF affects many tissues:
Lung Liver Pancreas Male Reproductive Tract Intestines Gall Bladder Sweat Gland
Why ferrets?
2 reasons:
Their lung anatomy and cell biology are similar to humans
They reproduce fast
Results
9 clones heterozygous for CFTR were bred
Expected 1:2:1 ratio to create ferret models with CF, or kits
Results
At 24 hours, CF kits were indestinguishable from littermates
At 36 hours, they failed to thrive
Euthanized at 48 hours
Results: MI Variable Penetrance MI affects the intestine
It is a blockage Can cause perforations in intestine
Frequency ranged for 50-100% in offspring of 9 heterzygous male parents Was statistically linked to the parents
used in breeding (P< 0.047)
Results: Male RT
Nearly all males with CF suffered from infertility
Vas Deferens becomes absent throughout development Unilateral degeneration detected as
early as 2 yrs old
Results: Pancreas All glands exhibited legions
Ferrets were consistant with those in newborn humans with CF
Significantly less severe than those seen on the Pig model
Histopathology of gall bladder and liver indistinguishable from non CF littermates
Results: Lungs Those infants that escaped MI did
not escape Lung complications
25% of neonatal deaths were not found out for those who passed MI
Evidence found of pneumonia and aspiration
Results: Lungs
ALT levels were elevated
Bilirubin Elevated
Cholesterol levels reduced Suggests potential liver disease No histo legions on liver, but elevated
LFTs
Results: Liver Elevated LFTs is unclear Bile acid malabsorption by intestine
Changes circulation and composition of bile acids
Cholesterol levels low due to defective fatty acid absorption in the gut
Oral doses of UDCA showed normalization of LFTs and ALT levels
Results: Nutrition Due to bad bile acids, lipids become
hard to digest in CF patients.
Due to impaired pancreas activity, HCO3- is not secreted into gut which lowers pH
To counteract, oral proton pump is given to try and normalize gut pH
Conclusions
There are many models out there
Each one may be best suited to a specific symptom of CF
Still doing research on ferrets for lungs Initial reasoning for using them is sound
References 1.) Disease phenotype of a ferret CFTR-knockout model of cystic
fibrosis Published in Volume 120, Issue 9 (September 1, 2010)J Clin Invest. 2010;120(9):3149–3160. doi:10.1172/JCI43052. Copyright © 2010, American Society for Clinical Investigation
2.) Riordan JR, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066–
1073. 3.) Egan ME. How useful are cystic fibrosis mouse models? Drug Discov
Today Dis Models. 2009;6(2):35–41.
4.) Rogers CS, et al. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science. 2008;321(5897):1837–1841.
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