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PubMed2001

Genetic association analysis of behavioral inhibition using candidate loci from mouse models.

Genes influence the development of anxiety disorders, but the specific loci involved are not known. Genetic association studies of anxiety disorders are complicated by the complexity of the phenotypes and the difficulty in identifying appropriate candidate loci. We have begun to examine the genetics of behavioral inhibition to the unfamiliar (BI), a heritable temperamental predisposition that is a developmental and familial risk factor for panic and phobic disorders. Specific loci associated with homologous phenotypes in mouse models provide compelling candidate genes for human BI. We conducted family-based association analyses of BI using four genes derived from genetic studies of mouse models with features of behavioral inhibition. The sample included families of 72 children classified as inhibited by structured behavioral assessments. We observed modest evidence of association (P = 0.05) between BI and the glutamic acid decarboxylase gene (65 kDA isoform), which encodes an enzyme involved in GABA synthesis. No significant evidence of association was observed for the genes encoding the adenosine A(1A) receptor, the adenosine A(2A) receptor, or preproenkephalin. This study illustrates the potential utility of using candidate genes derived from mouse models to dissect the genetic basis of BI, a possible intermediate phenotype for panic and phobic disorders.

Animals↗
PubMed2004

Mouse models of Alzheimer's disease: insight into treatment.

Mice overexpressing mutant Alzheimer's disease (AD)-related proteins exhibit many of the neuropathological and behavioral features of the human disease. Transgenic animals have been created that express mutations in the amyloid precursor protein (APP), presenilin (PS)1, and PS2, and also animals expressing more than one of these mutations. For example, in APP mouse models, there are age-related accumulations of amyloid-beta (Abeta)-containing neuritic plaques in the hippocampus and cerebral cortex, activation of astrocytes and microglial cells in regions containing plaques, and degeneration of cholinergic nerve terminals in brain regions that eventually become plaque containing. Missing in the APP and PS mouse models are neurofibrillary tangles and robust neuronal loss in cerebral cortical and subcortical regions such as the basal forebrain cholinergic and locus coeruleus noradrenergic nuclei. Neurofibrillary tangles can be produced in mice expressing mutant tau protein, and the tangle formation is further enhanced in animals that also express mutant APP. Studies in APP mouse models indicate that, like AD, there are abnormalities in adult hippocampal neurogenesis. The animal models of AD have been used to develop and test treatments that reduce brain levels of the Abeta42 protein, neuritic plaque load and glial activation, and some have been found to restore learning and memory function. If such treatments can be shown to stop the neurodegenerative process and restore hippocampal neurogenesis, damaged brain circuits may be replaceable in patients with AD.

Alzheimer Disease↗
PubMed1998

Nongenetic mouse models of non-insulin-dependent diabetes mellitus.

The purpose of the study was to develop a mouse model of non-insulin-dependent diabetes mellitus (NIDDM) that closely simulates the metabolic abnormalities of the human disease and is also cost-effective compared with the genetic models currently available. For this purpose, insulin resistance was induced in male C57BL/6J or Institute of Cancer Research (ICR) mice by feeding diets enriched in either fructose or fat, and hyperglycemia was induced by injecting these mice with a dose of streptozotocin (STZ) that does not cause diabetes in chow-fed mice. In the case of C57BL/6J mice, insulin levels initially increased in response to the fructose- and fat-enriched diets and then decreased to levels comparable to or still higher than those in chow-fed mice following STZ injection. Associated with the decrease in insulin levels following STZ, fat-fed and fructose-fed C57BL/6J mice became significantly hyperglycemic, reaching values of 388 +/- 38 and 366 +/- 58 mg/dL, respectively. In contrast, neither plasma glucose nor insulin concentrations changed in chow-fed mice injected with an identical amount of STZ. Essentially identical findings were seen before and after STZ injection in fat-fed compared with chow-fed ICR mice. Although a direct comparison was not made, sensitivity to the diabetogenic effects of STZ appeared to be greater in fat-fed ICR compared with fat-fed C57BL/6J mice. Finally, plasma glucose decreased when mice with these experimental models of NIDDM were treated with either metformin or tolbutamide. Given these results, it seems reasonable to suggest that the combination of dietary-induced insulin resistance and relatively low-dose STZ results in mouse models that should be of use in studying the pathophysiology of NIDDM or in evaluating therapeutic compounds for the treatment of NIDDM.

Animals↗
PubMed2006

[Establishment of transgenic mouse model of familial amyotrophic lateral sclerosis and identification of the filial generation].

OBJECTIVE: To establish transgenic mouse models of familial amyotrophic lateral sclerosis (FALS) and identify the genotype of the first filial generation. METHODS: Six male B6SJL SOD1G93A/+ hemizygote mice were mated with 6 female B6SJLF1/J+/+ mice to produce the filial generation. The genomic DNA was extracted from the tail vein blood of the first filial generation mice and PCR was performed to amplify the hmSOD1 gene fragment. The genotype of the mice was determined by electrophoresis, and the PCR product was purified for further gene sequence analysis and detection of mutation loci. RESULTS: Fifty-three progeny mice were born and the survival rate before ALS onset was 98% (52/53), and among the survived mice, the positivity rate for hmSOD1 gene was 44.2% (23/52). Electrophoresis result showed that the PCR product of 236 bp was consistent with the hmSOD1 gene fragment, and the sequence of the PCR product was identical with hmSOD1 gene sequence of G93A mutant. CONCLUSION: Transgenic mouse models of ALS can be established in the first filial generation of male B6SJL SOD1G93A/+ mice mated with female B6SJLF1/J+/+. PCR technique can precisely identify the genotype of the filial generation.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Comparison of a new pmp22 transgenic mouse line with other mouse models and human patients with CMT1A.

Charcot-Marie-Tooth disease type 1A is a dominantly inherited demyelinating disorder of the peripheral nervous system. It is most frequently caused by overexpression of peripheral myelin protein 22 (PMP22), but is also caused by point mutations in the PMP22 gene. We describe a new transgenic mouse model (My41) carrying the mouse, rather than the human, pmp22 gene. The My41 strain has a severe phenotype consisting of unstable gait and weakness of the hind limbs that becomes obvious during the first 3 weeks of life. My41 mice have a shortened life span and breed poorly. Pathologically, My41 mice have a demyelinating peripheral neuropathy in which 75% of axons do not have a measurable amount of myelin. We compare the peripheral nerve pathology seen in My41 mice, which carry the mouse pmp22 gene, with previously described transgenic mice over-expressing the human PMP22 protein and Trembler-J (TrJ) mice which have a P16L substitution. We also look at the differences between CMT1A duplication patients, patients with the P16L mutation and their appropriate mouse models.

Animals↗
PubMed2002

Demonstration of feasibility of in vivo gene therapy for Gaucher disease using a chemically induced mouse model.

Progress towards developing gene therapy for Gaucher disease has been hindered by the lack of an animal model. Here we describe a mouse model of Gaucher disease which has a chemically induced deficiency of glucocerebrosidase and that accumulates elevated levels of glucosylceramide (GL-1) in the lysosomes of Kupffer cells. Administration of mannose-terminated glucocerebrosidase (Cerezyme) resulted in the reduction of GL-1 levels in the livers of these animals. Gene transduction of hepatocytes with a plasmid DNA vector encoding human glucocerebrosidase (pGZB-GC) generated high-level expression and secretion of the enzyme into systemic circulation with consequent normalization of Kupffer cell GL-1 levels. This suggested that the de novo synthesized and unmodified enzyme produced by hepatocyte transduction was also capable of being delivered to the cells that are primarily affected in Gaucher disease. Immunolocalization studies also revealed that preferential transduction and expression of human glucocerebrosidase in the Kupffer cells with subsequent reduction in the GL-1 levels could be attained with a low dose of a recombinant adenoviral vector encoding the human enzyme (Ad2/CMV-GC). This observation raises the possibility of gene therapy for Gaucher disease that involves directly transducing the affected histiocytes using recombinant adenoviral vectors. Together, these data demonstrate the potential for use of in vivo gene therapy vectors for treating Gaucher disease.

Adenoviridae↗
PubMed1983

Effects of antiinflammatory agents on chronic Salmonella typhimurium infection in a mouse model.

Anti-inflammatory corticosteroids have been demonstrated to lower the resistance of the host to a range of infections in several different animal models. We have adapted the mouse model for Salmonella typhimurium infection, using a subcutaneous inoculation of 10(4) organisms in CBA/Ca mice. The chronic infection was potentiated by treatment with hydrocortisone given orally in the diet for up to 4 weeks, beginning on day 30 after infection. A dose of 25 mg/kg of body weight resulted in 100% mortality from Salmonella infection within 24 days of beginning hydrocortisone treatment. Nonsteroid drugs, indomethacin and a trial agent BW 755C, were compared with the corticosteroid in this model. No mortality was recorded during the 4 weeks of drug treatment in these groups. Fecal samples were monitored weekly, and drug-related effects on the normal fecal flora were observed. The kinetics of S. typhimurium infection were followed in both fecal and organ samples for the duration of the experiments. The model is useful for the determination of the lowered resistance of the host to infection after drug treatment and specifically demonstrated here the potential of the trial drug BW 755C as an active anti-inflammatory agent without one of the undesirable side effects of corticosteroids.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2000

A mouse model of renal tubular injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice.

Hereditary tyrosinemia type 1 (HT1) (McKusick 276700), a severe autosomal recessive disorder of tyrosine metabolism, is caused by mutations in the fumarylacetoacetate hydrolase gene Fah (EC 3.7.1.2), which encodes the last enzyme in the tyrosine catabolic pathway. HT1 is characterized by severe progressive liver disease and renal tubular dysfunction. Homozygous disruption of the gene encoding Fah in mice causes neonatal lethality (e.g., lethal Albino deletion c14CoS mice), an event that limits use of this animal as a model for HT1. A new mouse model was developed with two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd). The Fah-/- Hpd-/- mice grew normally without evidence of liver and renal disease, and the phenotype is similar to that in Fah+/+ Hpd-/- mice. The renal tubular cells of Fah-/- Hpd-/- mice, particularly proximal tubular cells, underwent rapid apoptosis when homogentisate, the intermediate metabolite between HPD and FAH, was administered to the Fah-/- Hpd-/- mice. Simultaneously, renal tubular function was impaired and Fanconi syndrome occurred. Apoptotic death of renal tubular cells, but not renal dysfunction, was prevented by pretreatment of the animals with YVAD, a specific inhibitor of caspases. In the homogentisate-treated Fah-/- Hpd-/- mice, massive amounts of succinylacetone were excreted into the urine, regardless of treatment with inhibitors. It is suggested that apoptotic death of renal tubular cells, as induced by administration of homogentisate to Fah-/- Hpd-/- mice, was caused by an intrinsic process, and that renal apoptosis and tubular dysfunctions in tubular cells occurred through different pathways. These observations shed light on the pathogenesis of renal tubular injury in subjects with FAH deficiency. These Fah-/- Hpd-/- mice can serve as a model in experiments related to renal tubular damage.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2000

Transgenic mouse models to study the role of the macrophage scavenger receptor class A in atherosclerosis.

Several in vivo studies have been performed on the role of the macrophage scavenger receptor class A (SR-A) in atherosclerosis using SR-A knockout mice. The results indicate both an antiatherogenic and a proatherogenic role of SR-A, depending on the nature of the animal model serving as the athero-susceptible background. To study the role of SR-A in a different model, we generated a transgenic mouse model with high level expression of the human SR-A gene using a 180 Kb yeast artificial chromosome (MSR1 transgenic mice). These mice show increased expression of SR-A according to the natural expression pattern. The MSR1 transgenic mice were crossed onto a low-density lipoprotein receptor deficient background and were fed a high fat diet for 10 weeks. After this period, the size of the atherosclerotic lesions in the proximal aorta was measured. Surprisingly, atherosclerosis was significantly reduced in the MSR1 transgenic mice. In a second study, the effect of SR-A was examined in APOE-3 Leiden mice providing a different athero-susceptible background. To exclude nonmacrophage effects, bone marrow was transplanted from MSR1 mice and wild-type littermates to APOE-3 Leiden transgenic mice. After 8 weeks on a high fat diet, atherosclerosis in the mice that had received MSR1 bone marrow was reduced compared with mice that had received wild-type bone marrow. This difference reached statistical significance when individual cholesterol exposure of the mice was taken into account. Both experiments indicated an antiatherogenic role of the SR-A. This observation cannot be explained easily by SR-A function in foam cell formation because in MSR1 macrophages in vitro foam cell formation is increased. Alternatively, however, SR-A may affect the activation of macrophages. Hence the response to lipopolysaccharide was measured in MSR1-transgenic macrophages. These macrophages showed a reduction in their activation in response to lipopolysaccharide, as measured by nitric oxide production. These data show that an elevated level of SR-A expression reduces atherosclerosis, potentially by modifying the response of macrophages to activation signals in the plaque.

Animals↗
PubMed1998

Salivary gland changes in the NOD mouse model for Sjögren's syndrome: is there a non-immune genetic trigger?

Sjögren's syndrome is a systemic autoimmune disease characterized by patient complaints of oral and ocular dryness accompanied by clinical observations of a progressive loss of salivary and lacrimal function, related to the presence of a focal, periductal leukocyte infiltrate. Progress in understanding the mechanisms involved in the development of autoimmune diseases in general, and Sjögren's syndrome specifically, has been generated as a result of renewed interest in animal models, such as the NOD mouse, which mimics autoimmune sialoadenitis. Biochemical analyses have indicated that the salivary glands have reduced beta-adrenergic, muscarinic, and neuropeptide signal transduction responses that correlate to reduced receptor density and the appearance of autoantibodies directed against these and other cell surface proteins. Using the NOD-scid mouse (lacking functional B- and T-lymphocytes) it has been determined that salivary flow rates are normal; however, these animals show abnormal changes in protein biosynthesis with increasing age. Histological evaluation of the submandibular gland from older NOD-scid mice revealed a loss of acinar cells accompanied by a potential increase in the ductal cell component of the tissue. Consistent with this finding, we recently have observed increased levels of cell death-associated cysteine proteases in the submandibular glands of 20 week NOD and NOD-scid mice but not in BALB/c and young NOD controls. Other novel protease activity was detected in the parotid and submandibular glands from NOD mice, which were able to generate the aberrantly processed PSP from purified BALB/c protein. Taken together, these data paint a complex picture of the development of Sjögren's syndrome-like disease in the NOD mouse model. The presence of activated lymphocytes appears to be necessary for the ultimate loss of exocrine gland function, potentially through the loss of tolerance to glandular proteins. However, the findings of high levels of apoptosis and aberrant protein expression in the submandibular gland in the absence of an immune response (NOD-scid) suggests that genetic alterations in glandular homeostasis involving the death program contribute to disease progression or even the initial trigger of autoimmunity.

Animals↗
PubMed2006

GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology.

Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion mutation within intron 1 of the FXN gene. However, the origins of the GAA repeat expansion, its unstable dynamics within different cells and tissues, and its effects on frataxin expression are not yet completely understood. Therefore, we have chosen to generate representative FRDA mouse models by using the human FXN GAA repeat expansion itself as the genetically modified mutation. We have previously reported the establishment of two lines of human FXN YAC transgenic mice that contain unstable GAA repeat expansions within the appropriate genomic context. We now describe the generation of FRDA mouse models by crossbreeding of both lines of human FXN YAC transgenic mice with heterozygous Fxn knockout mice. The resultant FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitase activity, and oxidative stress, leading to progressive neurodegenerative and cardiac pathological phenotypes. Coordination deficits are present, as measured by accelerating rotarod analysis, together with a progressive decrease in locomotor activity and increase in weight. Large vacuoles are detected within neurons of the dorsal root ganglia (DRG), predominantly within the lumbar regions in 6-month-old mice, but spreading to the cervical regions after 1 year of age. Secondary demyelination of large axons is also detected within the lumbar roots of older mice. Lipofuscin deposition is increased in both DRG neurons and cardiomyocytes, and iron deposition is detected in cardiomyocytes after 1 year of age. These mice represent the first GAA repeat expansion-based FRDA mouse models that exhibit progressive FRDA-like pathology and thus will be of use in testing potential therapeutic strategies, particularly GAA repeat-based strategies.

Aconitate Hydratase↗
PubMed2007

A mouse model of basal-like breast carcinoma with metaplastic elements.

Breast cancers arising in carriers of germline BRCA1 mutations frequently have a basal-like phenotype. Basal-like cancers are characterized by high histological grade, central necrotic areas, foci with metaplastic differentiation, lack of hormone receptor and HER2 (ErbB2) expression, and consistent positivity for basal markers, including CK5/6, CK14, and EGFR. We have used germline manipulation to generate a conditional mouse model of Brca1 deficiency. Transgenic expression of Cre recombinase in the mammary gland of these mice results in deletion of exons encoding the C-terminus of Brca1 and leads to tumour formation when combined with heterozygosity for a p53 mutation. Histologically, these mammary gland tumours were characterized by high histological grade, central necrotic areas, and presence of homologous metaplastic elements. These metaplastic elements consisted of neoplastic spindle cells or squamous cell differentiation in the form of keratin pearls or individual cell keratinization. Immunohistochemical analysis revealed expression of basal-like markers in all cases. The tumour phenotype generated in our mouse model was compared with published data on human basal-like breast carcinomas and also with metaplastic breast cancers with a basal-like phenotype; the comparison showed that we have generated a mouse model of basal-like breast cancer, which should prove useful in testing new and targeted treatments for this type of breast cancer.

Animals↗
PubMed1999

Contribution of genetically modified mouse models to the elucidation of bone physiology.

The development over the last few years of genetically modified mouse models has provided a wealth of new information on the intimate cellular mechanisms involved in bone physiology. This article reviews some of the new insights gained into non-collagenous bone proteins. The bone matrix is no longer viewed as a passive support for bone cells, but rather as a key factor in the regulation of cell recruitment, proliferation, and differentiation. Studies using genetically modified mouse models have demonstrated the central importance of transcription factors such as Cbfa1, c-Fos, and c-Src in the differentiation of osteoblasts or osteoclasts from bone marrow stem cells. They have also allowed to identify the main cytokines involved in the regulation of bone cell activities, particularly in estrogen-deprived individuals. A discussion is provided in this article of the studies that identified the main communication pathway between osteoblasts and osteoclasts, in which the mediators are osteoprotegerin and its ligand, and that demonstrated the central position of these two factors in the regulation of osteoclast differentiation and activity.

Animals↗
PubMed2006

Mouse models of cell cycle regulators: new paradigms.

In yeast, a single cyclin-dependent kinase (Cdk) is able to regulate diverse cell cycle transitions (S and M phases) by associating with multiple stage-specific cyclins. The evolution of multicellular organisms brought additional layers of cell cycle regulation in the form of numerous Cdks, cyclins and Cdk inhibitors to reflect the higher levels of organismal complexity. Our current knowledge about the mammalian cell cycle emerged from early experiments using human and rodent cell lines, from which we built the current textbook model of cell cycle regulation. In this model, the functions of different cyclin/Cdk complexes were thought to be specific for each cell cycle phase. In the last decade, studies using genetically engineered mice in which cell cycle regulators were targeted revealed many surprises. We discovered the in vivo functions of cell cycle proteins within the context of a living animal and whether they are essential for animal development. In this review, we discuss first the textbook model of cell cycle regulation, followed by a global overview of data obtained from different mouse models. We describe the similarities and differences between the phenotypes of different mouse models including embryonic lethality, sterility, hematopoietic, pancreatic, and placental defects. We also describe the role of key cell cycle regulators in the development of tumors in mice, and the implications of these data for human cancer. Furthermore, animal models in which two or more genes are ablated revealed which cell cycle regulators interact genetically and functionally complement each other. We discuss for example the interaction of cyclin D1 and p27 and the compensation of Cdk2 by Cdc2. We also focus on new functions discovered for certain cell cycle regulators such as the regulation of S phase by Cdc2 and the role of p27 in regulating cell migration. Finally, we conclude the chapter by discussing the limitations of animal models and to what extent can the recent findings be reconciled with the past work to come up with a new model for cell cycle regulation with high levels of redundancy among the molecular players.

Animals↗
PubMed2005

Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis.

Pseudomonas aeruginosa causes a chronic infection in the lungs of cystic fibrosis (CF) patients by establishing an alginate-containing biofilm. The infection has been studied in several animal models; however, most of the models required artificial embedding of the bacteria. We present here a new pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion in mucA and functional N-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF mice (Cftr(tmlUnc-/-)) and BALB/c mice, as reflected by the detection of a high number of P. aeruginosa organisms in the lung homogenates at 7 days postinfection and alginate biofilms, surrounded by polymorphonuclear leukocytes in the alveoli. In comparison, both an AHL-producing nonmucoid revertant (NH57388C) from the mucoid isolate (NH57388A) and a nonmucoid isolate (NH57388B) deficient in AHL were almost cleared from the lungs of the mice. This model, in which P. aeruginosa is protected against the defense system of the lung by alginate, is similar to the clinical situation. Therefore, the mouse model provides an improved method for evaluating the interaction between mucoid P. aeruginosa, the host, and antibacterial therapy.

Alginates↗
PubMed2002

Beethoven, a mouse model for dominant, progressive hearing loss DFNA36.

Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven (Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn) are mouse models, respectively.

Animals↗
PubMed2001

Blockade of caspases inhibits amebic liver abscess formation in a mouse model of disease.

We looked at the effect of inhibiting caspases on amebic liver abscess in the mouse model of infection. A dose of the pan-caspase inhibitor benzyloxycarbonyl-V-A-D-O-methyl fluoromethyl ketone (Z-VAD-FMK; R & D Systems) given to SCID mice 2 h prior to direct hepatic inoculation with Entamoeba histolytica trophozoites, and 12 h after amebic inoculation, reduced the mean liver abscess size by 70% at 24 h compared to a control group. These data indicate that apoptosis plays a significant but not an exclusive role in amebic liver abscess formation in the mouse model.

Amino Acid Chloromethyl Ketones↗
PubMed2002

[A mouse model of severe acute pancreatitis induced by caerulein plus lipopolysaccharide].

OBJECTIVE: To set up a convenient nontraumatic mouse model of severe acute pancreatitis(SAP). METHODS: Mice received intraperitoneal injections with caerulein and lipopolysaccharide (LPS). Serum amylase and pancreatic moisture content were measured during experiment. The histo pathological changes of pancreas and relevant organs were observed under light microscope. RESULTS: Serum amylase and pancreatic moisture content increased and pancreatic interstitial edema, inflammatory cellular infiltration, parenchymal necrosis as well as parenchymal hemorrhages were happened in the caerulein plus LPS group, and the lesions of other organs including stomach, ileum, spleen, and lung were seen as well. In the careulein group, there was only pancreatic interstitial edema with no parenchmal necrosis or hemorrhage, and the rest organs were normal. CONCLUSIONS: The SAP mouse model induced by caerulein plus LPS has the same pathological characteristics of human SAP, which can be used for human SAP studies.

Animals↗