Analysis Tools
mortality/aging
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• mutants exhibit a decrease in survival (7 days vs. 13 days in wild-type) when challenged with Salmonella enterica serovar Typhimurium
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• 50% reduction in life span, with viability declining between 27 and 65 weeks of age
• mice that die within this time frame, die suddenly, without any visible signs of disease
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respiratory system
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• reactive endothelial cell proliferation
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• hyperemic lungs
• alveolar spaces are filled with extravasated red blood cells
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• increase in inflammatory infiltrates in the lung
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• parenchymal hypercellularity
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cardiovascular system
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• reactive endothelial cell proliferation
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• myocardium is thickened in both the left and right ventricles at 12 months of age
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• myocyte hypertrophy and disorganization
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• increase in intraventricular septal thickness during diastole
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• 12 month old mice show thickening of the myocardium in both ventricles and generalized myocyte hypertrophy
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• 12 month old mutants exhibit concentric left ventricular hypertrophy
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• about 18% and 36% increase in left ventricular wall thickness at 4 and 12 months of age, respectively
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• the right ventricular chamber is about 70% and 25% larger than in wild-type at 4 and 12 months of age, respectively
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• increase in fibrosis at 12 months of age
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• hyperemic lungs
• alveolar spaces are filled with extravasated red blood cells
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• 29% decrease in fractional shortening at 12 months of age, indicating reduction in left ventricular systolic fraction
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• impaired response to phenylephrine (PE) due to increased Nos3 activity
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• impaired acetylcholine induced relaxation of the aortic rings
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• severe right-sided heart failure
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cellular
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• adipocytes from peri-gonadal white adipose tissue show barren membrane architecture indicating a loss of caveolae
(J:75192)
• endothelial cells lack caveolae membranes
(J:75193)
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• uptake and transport of albumin from the blood to the interstitium by endothelial cells is defective due to absence of caveolae
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homeostasis/metabolism
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• plasma glucose, insulin, and cholesterol levels were similar to wild-type in both fasting and post-prandial states at 12 weeks of age, standard chow diet
• mutants do not exhibit significant changes in paremeters of energy expenditure such as VO2, VCO2, respiratory quotient, heat release, or movement, indicating that leanness is not due to increased energy expenditure
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• exercise intolerance when compared to wild-type in a swimming test
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• transvascular protein transport is increased, with mutants showing higher albumin and IgM clearance from the plasma to peritoneium, and increased clearance of high molecular weight Ficoll
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• mutants are resistant to obesity when challenged with a high fat diet for 36 weeks
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• plasma ACRP30 (an adipocyte secreted factor) levels are reduced by 8-10 fold
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• plasma leptin levels are reduced more than 2-fold
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• lungs exhibit increased NOS3 (eNOS)-derived nitric oxide production and impaired NOS2 (iNOS)-derived nitric oxide production after LPS challenge
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• mutants show kinetically delayed clearance of triglycerides in an oral fat tolerance test
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• free fatty acids levels fail to undergo the expected post-eating reduction seen in wild-type
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• triglyceride levels are elevated in the fasted state and increased even more post-prandially, due to perturbed lipoprotein lipase activity
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• the chylomicron/VLDL fraction of triglycerides is increased during fasting and increases dramatically above wild-type mice in the post-prandial state
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• increased production of CXCL10 at 3 days post Salmonella infection
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• increased production of interferon-gamma at 3 days post Salmonella infection
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• increased production of IL-6 at 3 days post Salmonella infection
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• increased production of TNF-alpha at 3 days post Salmonella infection
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• mutants are more susceptible to DMBA (7,12-dimethylbenzanthracene)-induced skin carcinogenesis
• 100% of mice develop tumors at 12 weeks of age compared to 10% of wild-type mice
• tumor multiplicity is greatly increased
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• mutants exhibit an increase of cerebral volume of infarction compared to wild-type, with fewer numbers of proliferating endothelial cells and increased numbers of cells undergoing apoptotic cell death in ischemic brains
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muscle
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• myocardium is thickened in both the left and right ventricles at 12 months of age
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• myocyte hypertrophy and disorganization
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• 12 month old mutants exhibit concentric left ventricular hypertrophy
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• 29% decrease in fractional shortening at 12 months of age, indicating reduction in left ventricular systolic fraction
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• impaired response to phenylephrine (PE) due to increased Nos3 activity
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• impaired acetylcholine induced relaxation of the aortic rings
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• skeletal muscle fibers of males exhibit and increase in tubular aggregate formation with age
• sarcoplasmic reticulum is dilated in skeletal muscle of males
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endocrine/exocrine glands
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• size of mammary glands is reduced, however overall architecture is intact
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• mammary epithelial cell hyperplasia, even in 6 week old virgin mice
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• the number of mammary ducts per field is increased
• the mammary ductal epithelia exhibits hyperproliferation
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• intraductal hyperplasia, with the epithelial cell layer 3-4 cells thick
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• mammary epithelial cell hyperplasia, even in 6 week old virgin mice
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neoplasm
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• mice fail to spontaneously develop mammary tumors, even at up to 9 months of age, although mammary glands at this age show pronounced lobular development with numerous acini per terminal ductal lobular unit, hyperplasia of the mammary epithelial lining, and fibrosis
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• mutants are more susceptible to DMBA (7,12-dimethylbenzanthracene)-induced skin carcinogenesis
• 100% of mice develop tumors at 12 weeks of age compared to 10% of wild-type mice
• tumor multiplicity is greatly increased
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immune system
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• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures
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• polymorphonuclear neutrophil (PMN) sequestration in lungs is reduced in mutants compared to wild-type after LPS challenge
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• mutants lack infiltration of white pulp by neutrophils when infected with Salmonella
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• macrophages exhibit increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS
• macrophages show no differences in the uptake of opsonized bacteria from wild-type
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• increased production of CXCL10 at 3 days post Salmonella infection
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• increased production of interferon-gamma at 3 days post Salmonella infection
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• increased production of IL-6 at 3 days post Salmonella infection
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• increased production of TNF-alpha at 3 days post Salmonella infection
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• increased production of the chemokines CCL3, CXCL1 and CXCL10 at 3 days post Salmonella infection
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• mutants show reduced mortality compared to wild-type mice following LPS challenge due to elevated nitric oxide as mutants treated with an NOS3 inhibitor show 100% mortality
• lungs are protected from LPS-induced lung injury, showing no increase in lung microvascular permeability or edema formation as in wild-type mice
• adhesion of wild-type PMN to mutant endothelial cells is reduced after LPS challenge
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• increase in inflammatory infiltrates in the lung
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• mutants exhibit increased production of inflammatory cytokines, chemokines, and nitric oxide in response to Salmonella infection but are unable to control the systemic infection and have higher bacterial burden in spleen and liver
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• mutants exhibit a decrease in survival (7 days vs. 13 days in wild-type) when challenged with Salmonella enterica serovar Typhimurium
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nervous system
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• mutants exhibit an increase of cerebral volume of infarction compared to wild-type, with fewer numbers of proliferating endothelial cells and increased numbers of cells undergoing apoptotic cell death in ischemic brains
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hematopoietic system
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• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures
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• polymorphonuclear neutrophil (PMN) sequestration in lungs is reduced in mutants compared to wild-type after LPS challenge
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• mutants lack infiltration of white pulp by neutrophils when infected with Salmonella
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• macrophages exhibit increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS
• macrophages show no differences in the uptake of opsonized bacteria from wild-type
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skeleton
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• marrow cultures from mutants generate about 20% more osteoclasts than wild-type cultures
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• 58.4% increase in ephiphyseal bone volume at 5 weeks
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• 77.4 % increase in metaphyseal bone volume at 8 weeks but not at 5 weeks of age
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• 33% increase in stiffness and 33% decrease in postyield deflection of cortical bone
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• at the femoral mid-diaphysis, the total cortical area is increased by 19.7% and 13.8%, at 5 and 8 weeks of age, respectively, with expanded periosteal and endocortical surfaces at 8 weeks
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• metaphyseal trabeculae are greater in number and show reduced spacing, however trabecular thickness is not different from wild-typ
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• increase in trabecular number in the distal femoral epiphysis
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• increase in thickness of the distal femoral epiphysis
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• mineral apposition rate is increased at both metaphyseal and cortical sites at 5 weeks of age and regresses by 8 weeks of age
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• increase in bone formation rate at the trabecular and cortical sites at 5 weeks of age
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• stiffer bone capable of bearing a greater load before failure
• 25% increase in maximum force
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adipose tissue
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• mutants on a high fat diet exhibit hyperplastic brown adipose tissue, putatively secondary to elevated triglyceride levels
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• the hypodermal fat layer is absent in both males and females at 12 weeks of age
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• underdeveloped subcutaneous fat pads
• at 36 weeks of age on a high fat diet, subcutaneous fat is severely perturbed in females, with reduced numbers of adipoctyes that are heterogeneous in size and marked interstitial fibrosis and hypercellularity
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• at 12 weeks of age on a high fat diet, mutants exhibit a 2-fold reduction in female mammary gland/subcutaneous WAT
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• 2-fold reduction in the fat-to-water ratio
• at 35 weeks of age on a high fat diet, mutants only show minor gains in fat mass compared to wild-type and have dramatically reduced adiposity in all fat pads compared to wild-type
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• at 12 weeks of age, female mammary gland 4/subcutaneous adipocytes contain reduced lipid droplets
• lipid droplet size in adipoctyes is about 2-3-fold smaller than in wild-type
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• lipid droplet size in adipoctyes is about 2-3-fold smaller than in wild-type
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• underdeveloped peri-gonadal fat pads
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• at 36 weeks of age on a high fat diet, mammary gland 4 fat is severely perturbed in females, with reduced numbers of adipoctyes that are heterogeneous in size and marked interstitial fibrosis and hypercellularity
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behavior/neurological
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• daily food intake is higher in females
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• exercise intolerance when compared to wild-type in a swimming test
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growth/size/body
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• 12 month old mice show thickening of the myocardium in both ventricles and generalized myocyte hypertrophy
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• 12 month old mutants exhibit concentric left ventricular hypertrophy
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• mice are leaner than wild-type mice on a chow diet
• relative decrease in weight is exacerbated on a high fat diet
• resistance to diet-induced obesity due to an inability to convert lipoprotein triglycerides into the fat droplet storage form
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• lack of weight gain
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• mutants are resistant to obesity when challenged with a high fat diet for 36 weeks
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liver/biliary system
| N |
• livers show no increase in weight or steatosis
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integument
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• the hypodermal fat layer is absent in both males and females at 12 weeks of age
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• underdeveloped subcutaneous fat pads
• at 36 weeks of age on a high fat diet, subcutaneous fat is severely perturbed in females, with reduced numbers of adipoctyes that are heterogeneous in size and marked interstitial fibrosis and hypercellularity
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• size of mammary glands is reduced, however overall architecture is intact
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• mammary epithelial cell hyperplasia, even in 6 week old virgin mice
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• the number of mammary ducts per field is increased
• the mammary ductal epithelia exhibits hyperproliferation
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• intraductal hyperplasia, with the epithelial cell layer 3-4 cells thick
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• mammary epithelial cell hyperplasia, even in 6 week old virgin mice
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• mutants develop extensive epidermal hyperplasia in response to DMBA treatment before tumor formation
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limbs/digits/tail
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• at the femoral mid-diaphysis, the total cortical area is increased by 19.7% and 13.8%, at 5 and 8 weeks of age, respectively, with expanded periosteal and endocortical surfaces at 8 weeks
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hypertrophic cardiomyopathy | DOID:11984 | J:87282 | ||
