Analysis Tools
mortality/aging
| N |
• Background Sensitivity: unlike homozygotes of a mixed genetic background, homozygotes on a congenic C57BL/6 background do not succumb to morbidity through lung dysfunction
(J:92948)
(J:102205)
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• at 144 hrs after partial hepatectomy, 4 of six 9-12-wk-old homozygotes become moribund and the remaining 2 show decreased liver to body mass ratios whereas all wild-type mice appear healthy with normal liver body mass ratios
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immune system
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• at 12 weeks, homozygotes exhibit a 1.8-fold increase in TNF converting enzyme activity (ADAM17), as well as constitutive release of TNF and activation of TNF signaling in the liver
• in hepatic sinusoids, constitutive TNF shedding is detected in Kupffer cells, the resident macrophages of the liver
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• aging homozygotes display progressive hepatic inflammation with periportal lymphocytic infiltrates that are neither clonogenic nor tumoral
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liver/biliary system
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• after partial hepatectomy, necrosis in regenerating livers is accompanied by increased TNF activity and hepatocyte apoptosis
• hepatocyte cell death is fully rescued by a neutralizing antibody to TNF
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• at 18-22 months, homozygotes display hepatic necrosis; however, no excessive collagen deposition or fibrosis is observed
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• aging homozygotes display progressive hepatic inflammation with periportal lymphocytic infiltrates that are neither clonogenic nor tumoral
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• aging homozygotes exhibit major progressive changes in periportal lobular architecture
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• following partial hepatectomy, all 9-12 week-old homozygotes show a significant reduction in liver to body mass ratio
• failure of liver regeneration occurs despite accelerated progression of the cell cycle in mutant hepatocytes
• by 72 hours, regenerating livers of homozygotes show multiple foci of necrosis; extensive hepatocyte vacuolization is noted by 144 hours
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respiratory system
| N |
• unlike the original mixed strain, C57BL/6 homozygotes do not succumb to morbidity through lung dysfunction
(J:92948)
(J:102205)
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• as early as E12.5, homozygotes display reduced bronchiole branching relative to wild-type
• in vitro, E11.5 homozygotes possess only 62% of peripheral terminal buds found in wild-type
• gelatin and in situ zymography indicated enhanced MMP-mediated degradation of fibronectin in the basement membrane and in the stroma surrounding the developing bronchiole epithelium
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• lungs from newborn homozygotes display deficient alveolarization relative to wild-type
(J:85546)
• defective alveologenesis putatively due to excessive matrix metalloproteinase (MMP) activity and inappropriate ECM degradation in the developing lung
(J:161579)
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• at P1-P14 (early alveologenesis), mutant alveolar walls appear to be thinner than wild-type controls
• however, no significant differences in collagen content are observed during sacculation or alveologenesis, as determined by
trichrome staining of alveolar walls
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• airspaces are already dilated at birth (P1) and continue to increase in size over the course of early alveolarization (P5-P14)
• mutant alveoli are 26% larger at P1, 27% larger at P5, 32% larger at P9, and 43% larger at P14 relative to wild-type controls
• gelatin zymography revealed a significant increase in abundance of active MMP2 in mutant lung extracts at P1 (180%) and P5 (150%) but not later
• injection of mutant pregnant dams with a synthetic metalloproteinase inhibitor (GM6001) on E16.5 results in mutant pups with a modest but significant reduction in mean alveolar size at P1 but not at P14
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• lungs from newborn homozygotes display dilated terminal buds
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cardiovascular system
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• exhibit a significant loss of perimysial collagen fibers in hearts and a reduction in the fiber connectivity of the collagen network
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• heart-to-body weight ratio is higher at 21 months of age, accompanied by increased cardiomyocyte cross-sectional area indicating cardiomyocyte hypertrophy
• cardiomyocyte hypertrophy becomes evident at 16 months of age
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• left ventricular volume is increased at 21 months of age
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• exhibit features of human dilated cardiomyopathy, including chamber dilation, cellular hypertrophy without myocardial wall thickening, and impaired contractile performance
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• with aging, exhibit a reduction in + dP/dt and diminished fractional shortening indicating impaired ventricular contractility
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• with age, exhibit a reduction in dP/dt and an increase in tau suggesting delayed ventricular relaxation
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• with age, exhibit reduction in left ventricular developed pressure
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• with age, exhibit reductions in left ventricular peak systolic pressure
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growth/size/body
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• heart-to-body weight ratio is higher at 21 months of age, accompanied by increased cardiomyocyte cross-sectional area indicating cardiomyocyte hypertrophy
• cardiomyocyte hypertrophy becomes evident at 16 months of age
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muscle
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• exhibit features of human dilated cardiomyopathy, including chamber dilation, cellular hypertrophy without myocardial wall thickening, and impaired contractile performance
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• with aging, exhibit a reduction in + dP/dt and diminished fractional shortening indicating impaired ventricular contractility
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• with age, exhibit a reduction in dP/dt and an increase in tau suggesting delayed ventricular relaxation
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cellular
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• after partial hepatectomy, necrosis in regenerating livers is accompanied by increased TNF activity and hepatocyte apoptosis
• hepatocyte cell death is fully rescued by a neutralizing antibody to TNF
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• at 18-22 months, homozygotes display hepatic necrosis; however, no excessive collagen deposition or fibrosis is observed
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:102205 | |
