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At least 109 records · Page 6Linked to original sources
PubMed1995

Developmental hematopoiesis from prenatal to young-adult life in the mouse model.

Five measurements of hematopoietic function were made in the mouse from midfetal life to young adulthood. These included two in vivo (day-8 colony-forming unit-spleen [CFU-S8] and day-12 CFU-S [CFU-S12]) and two in vitro clonal measurements of hematopoietic stem and progenitor cells (high proliferative potential colony-forming cell [HPP-CFC] and CFC of low proliferative potential [LPP-CFC]) as well as an in vitro clonal measurement of colony-forming unit-fibroblast (CFU-F). The appearance, increase, subsequent decrease, and later emergence and increase of each of these parameters in the fetal-liver, newborn, growing-infant, and young-adult bone marrow were correlated and found to be in parallel. Exceptions to this included the earlier appearance in the fetal liver of CFU-F and the relatively differentiated hematopoietic LPP-CFC. The pattern of emergence of these progenitor cell subpopulations in the fetal liver may be related, in part to the timing of the hematopoietic microenvironment development and the relative frequencies of progenitor cell types in the circulation. This developmental study in the mouse model describes additional correlations between in vivo and in vitro colony-forming stem cells and fibroblastic stromal colony-forming cells, and it suggests the dependence of hematopoietic stem cells upon the stromal microenvironment for the necessary conditions for hematopoietic stem cell lodgment, growth, and maturation.

Aging↗
PubMed1995

Analyses of homologous rotavirus infection in the mouse model.

The group A rotaviruses are significant human and veterinary pathogens in terms of morbidity, mortality, and economic loss. Despite its importance, an effective vaccine remains elusive due at least in part to our incomplete understanding of rotavirus immunity and protection. Both large and small animal model systems have been established to address these issues. One significant drawback of these models is the lack of well-characterized wild-type homologous viruses and their cell culture-adapted variants. We have characterized four strains of murine rotaviruses, EC, EHP, EL, and EW, in the infant and adult mouse model using wild-type isolates and cell culture-adapted variants of each strain. Wild-type murine rotaviruses appear to be equally infectious in infant and adult mice in terms of the intensity and duration of virus shedding following primary infection. Spread of infection to naive cagemates is seen in both age groups. Clearance of shedding following primary infection appears to correlate with the development of virus-specific intestinal IgA. Protective immunity is developed in both infant and adult mice following oral infection as demonstrated by a lack of shedding after subsequent wild-type virus challenge. Cell culture-adapted murine rotaviruses appear to be highly attenuated when administered to naive animals and do not spread efficiently to nonimmune cagemates. The availability of these wild-type and cell culture-adapted virus preparations should allow a more systematic evaluation of rotavirus infection and immunity. Furthermore, future vaccine strategies can be evaluated in the mouse model using several fully virulent homologous viruses for challenge.

Animals↗
PubMed2026

Motor coordination and behavioural deficits in a mouse model of KMT2B-related dystonia.

INTRODUCTION: Pathogenic variants in KMT2B cause early-onset dystonia, but a mouse model that has undergone comprehensive, dystonia-oriented phenotyping is lacking. METHODS: We conducted detailed phenotyping on heterozygous Kmt2b constitutive knockout mice and wild-type littermates, assessing growth, neurobehavioural traits, motor coordination, sensorimotor gating, social behaviour and metabolic parameters, combined with striatal RNA sequencing. RESULTS: Kmt2b knockout mice of both sexes were viable but significantly smaller and lighter than littermate controls. Knockouts were hyperlocomotive in the open field and showed approximately two-fold larger acoustic startle responses; unexpectedly, prepulse inhibition was enhanced rather than reduced at all prepulse intensities. On the balance beam, knockouts crossed more slowly and paused more frequently; female knockouts also paused more on the ladder rung task. Frame-by-frame video analysis revealed a claw-like hindpaw posture characterized by abnormal inward flexion of the digits. Knockout mice spent less time investigating a novel conspecific, while social recognition memory remained intact. Striatal RNA sequencing confirmed reduction of Kmt2b transcript to approximately half of control levels and identified 177 differentially expressed genes, including Maob, encoding monoamine oxidase B; gene set enrichment analysis implicated neurodevelopmental, glial and mitochondrial processes. Nociception, vision, body-weight-adjusted grip strength, and clinical chemistry and haematological measures were largely unaffected. CONCLUSION: Heterozygous Kmt2b knockout mice show hyperlocomotion, altered sensorimotor gating, impaired motor coordination with dystonic-like paw posturing and reduced sociability, alongside a striatal transcriptomic signature implicating neurodevelopmental processes. The model mirrors aspects of human KMT2B-related dystonia and provides a platform for mechanistic study; environmental or pharmacological challenge may be needed to unmask overt dystonic features.

Dystonia↗
PubMed1994

Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited human diseases in which photoreceptor degeneration leads to visual loss and eventually to blindness. Although mutations in the rhodopsin, peripherin, and cGMP phosphodiesterase genes have been identified in some forms of RP, it remains to be determined whether these mutations lead to photoreceptor cell death through necrotic or apoptotic mechanisms. In this paper, we report a test of the hypothesis that photoreceptor cell death occurs by an apoptotic mechanism in three mouse models of RP: retinal degeneration slow (rds) caused by a peripherin mutation, retinal degeneration (rd) caused by a defect in cGMP phosphodiesterase, and transgenic mice carrying a rhodopsin Q344ter mutation responsible for autosomal dominant RP. Two complementary techniques were used to detect apoptosis-specific internucleosomal DNA fragmentation: agarose gel electrophoresis and in situ labeling of apoptotic cells by terminal dUTP nick end labeling. Both methods showed extensive apoptosis of photoreceptors in all three mouse models of retinal degeneration. We also show that apoptotic death occurs in the retina during normal development, suggesting that different mechanisms can cause photoreceptor death by activating an intrinsic death program in these cells. These findings raise the possibility that retinal degenerations may be slowed by interfering with the apoptotic mechanism itself.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1985

Anticonvulsant action of GABA agonists and prodrugs on minor and major seizures in epileptic gerbils. Comparison with mouse models of seizure states.

The anticonvulsant efficacy of the GABAmimetic drugs cetyl GABA, progabide and THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) was studied against minor (myoclonic) and major (generalized tonic-clonic) seizures in gerbils as well as against maximal electroshock and s.c. pentylenetetrazol-induced seizures in mice. Seizures in gerbils were evoked by a blast of compressed air. THIP and progabide were about equally active to protect gerbils against minor and major seizures. ED 50s for THIP were 0.98 and 1.3 mg/kg and for progabide 58 and 50 mg/kg i.p., respectively. Cetyl GABA failed to show a linear dose-response against minor seizures but was quite potent against major ones (ED 50 4.4 mg/kg). All three GABAmimetics were inactive in the mouse models of seizure states except a weak effect of progabide against maximal electroshock seizures. The data show that seizure-prone gerbils with different seizure types differ strikingly in sensitivity to GABAmimetic drugs from traditional mouse models for anticonvulsant drug evaluation.

Animals↗
PubMed1990

The relationship of excess copper accumulation by fibroblasts from the brindled mouse model of Menkes disease to the primary defect.

Fibroblasts from the brindled mouse model of Menkes disease are known to accumulate excess copper. Most of the copper in the cytosol of these fibroblasts is bound to metallothionein (MT), which is elevated in Menkes or brindled mouse fibroblasts. Copper accumulation by normal fibroblasts containing excess MT was examined to determine if the excess copper accumulation phenotype was secondary to excess MT or associated with the primary defect in fibroblasts from the brindled mice. MT was induced in normal fibroblasts by copper, zinc or dexamethasone to levels comparable with those in brindled mice fibroblasts, as determined by radioimmunoassays. Normal fibroblasts containing excess MT accumulate copper normally, i.e. they do not exhibit the excess copper accumulation phenotype. Consistent with this result, copper efflux from normal fibroblasts containing excess MT was also normal. The data suggest that one function of the protein associated with the primary defect is to help determine how much copper is taken up and retained by fibroblasts and other cell types exhibiting the excess copper phenotype in Menkes disease. The capacity of this protein is apparently exceeded in normal fibroblasts if serum or albumin is not present extracellularly to limit total copper uptake. Consistent with a defect in an intracellular protein, the kinetics of copper transport by brindled mice fibroblasts were found to be normal.

Animals↗
PubMed1989

Radioimmunoscintigraphy and radioimmunotherapy in nude mouse models. Studies with site-specifically modified monoclonal antibodies.

Site-specific covalent modification of monoclonal antibodies at the oligosaccharide offers advantages over more conventional modification processes that involve direct attachment at tyrosine, lysine or glutamic/aspartic acid side chains. Using the site-specific modification process, attachment sites on the antibody are distal to the antigen-binding region. Thus, homogeneity of antigen-binding properties and affinity for the unmodified protein are preserved. Furthermore, higher derivatization ratios with no resultant loss of immunoreactivity can be achieved for monoclonal antibodies modified at the oligosaccharide. In vivo biodistribution and tumor localization studies in nude mouse models suggest that antibodies radiolabeled at their oligosaccharide might represent improved immunoscintigraphic reagents. In a variety of tumor xenograft models, site-specific modified 111In-labeled antibody conjugates localized to the tumor site with little non-specific localization in other tissues or organs. The degree of localization at the target site was substantially greater than that of 111In-labeled antibodies directly modified at the tyrosine side chain. Preliminary studies with 212Bi- and 90Y-labeled antibodies modified at the oligosaccharide indicate that both of these radioisotopes have immunotherapeutic potential. Because of its preferential uptake by the kidney, the use of 212Bi may be best suited for tumors localized within the peritoneal cavity, such as ovarian and colorectal carcinomas. The toxicity of 90Y at high specific activities suggests that a regimen of repeated smaller doses of this radioisotope is best suited for therapeutic use. Studies in tumor-bearing mouse models are currently underway to better define the optimal dosage and administration regimens for both of these radioisotopes when attached to site-specific modified antibodies.

Animals↗
PubMed2026

Optimized AAV5-RPGR ORF15 Gene Therapy Rescues Photoreceptor Structure and Function in X-Linked Retinitis Pigmentosa Mouse Model.

PURPOSE: To develop and evaluate an rAAV5-based gene therapy vector expressing an optimized human RPGR ORF15 transgene (rAAV5-RPGR) for the treatment of X-linked retinitis pigmentosa caused by RPGR mutations, addressing the challenges of cloning the unstable wild-type ORF15 sequence. DESIGN: This was a prospective experimental study. SUBJECTS: This was an animal study. METHODS: An optimized RPGR ORF15 sequence was designed to eliminate problematic secondary structures and cryptic splice sites. In vitro expression was validated in HEK 293T and photoreceptor-like 661 W cells. A complete Rpgr knockout mouse model (Rpgr-knockout [KO]) was generated and characterized phenotypically. Therapeutic efficacy was assessed in Rpgr-KO mice via subretinal injection of rAAV5-RPGR at low (1 &#xd7; 10&#x2079; vg/eye), medium (3 &#xd7; 10&#x2079; vg/eye), or high (1 &#xd7; 10&#xb9;&#x2070; vg/eye) doses. Structural and functional outcomes were evaluated at 12- and 14-month postinjection. Short-term safety was assessed in rabbits 1 month after subretinal injection. MAIN OUTCOME MEASURES: Level of RPGR protein expression and Protein isoform profile (elimination of truncated isoforms), Cellular localization of transgene expression and Dose-dependence of expression, outer nuclear layer thickness, and electroretinography parameters. RESULTS: (1) The optimized vector increased RPGR protein expression 3.3-fold in vitro compared to wild-type and eliminated truncated isoforms. (2) Subretinal delivery of rAAV5-RPGR in mice demonstrated dose-dependent transgene expression localized correctly to photoreceptor inner segments. (3) In Rpgr-KO mice, high-dose treatment significantly preserved outer nuclear layer thickness at the injection site (42% greater than controls at 14 months, P < .01) and central retina (P < .05), reduced aberrant rhodopsin mislocalization (P < .01), and partially restored retinal function. ERG showed significantly improved scotopic a-wave (&#x2265;100 vs <90 &#xb5;V in controls at 10 cd&#xb7;s/m&#xb2;) and photopic b-wave amplitudes (49-66 vs 31-46 &#xb5;V at 30 cd&#xb7;s/m&#xb2;) in treated mice. (4) No vector-related toxicity was observed in rabbits. CONCLUSIONS: rAAV5-RPGR mediated efficiently, targeted expression of optimized RPGR-ORF15, significantly preserved photoreceptor structure and function in a severe X-linked retinitis pigmentosa mouse model, and demonstrated a favorable safety profile. This study provides preclinical proof-of-concept for RPGR-targeted gene replacement therapy.

Animals↗
PubMed1988

Acellular pertussis vaccines: evaluation of reversion in a nude mouse model.

An animal model has been developed to assess the safety of acellular pertussis vaccines in terms of reversion to toxicity. Adsorbed pertussis toxoid preparations, alone or combined in a DTP formulation, were administered to nude mice intraperitoneally. In parallel, groups of positive and negative control mice received pertussis toxin and buffer, respectively. The circulating white blood cells of the animals were monitored for 28 days. Mice immunized with glutaraldehyde toxoid preparations did not develop a lymphocytosis during the observation period, whereas mice immunized with an experimental formalin pertussis toxoid vaccine exhibited a high lymphocytosis six days after vaccine administration, demonstrating, in this model, a reversion of the toxoid. The nude mouse model thus appears to reveal the in-vivo reversion of pertussis toxoids and could be included in the quality control panel for the assessment of the safety of acellular pertussis vaccine.

Animals↗
PubMed2026

Phosphoproteomic analysis in a mouse model reveals ERK signaling as a key modulator of inflammatory response in nasal mucosa associated with childhood allergic rhinitis.

Childhood allergic rhinitis (AR) is a multifactorial condition arising from the interplay between genetic predisposition and environmental exposures. Although protein phosphorylation is widely recognized as a key regulator of gene expression across various physiological and pathological states, its global alterations in the nasal mucosa of pediatric patients with AR and their subsequent impact on mucosal function and inflammatory pathways remain incompletely characterized. Our study aimed to elucidate the molecular mechanisms underlying nasal mucosa dysfunction induced by pediatric AR. Our analysis revealed 3,861 proteins encompassing a total of 15,491 phosphorylation sites. Specifically, we detected 441 downregulated phosphorylation sites on 584 proteins and 531 upregulated phosphorylation sites on 722 proteins in the nasal mucosa of the AR group. Our proteomics findings suggest that the dysregulation of immune activation and metabolic regulation may contribute to AR pathophysiology. Through pathway analysis of the identified phosphorylation sites, we found Extracellular Signal-Regulated Kinase (ERK) signaling emerged as an important pathway; notably, upregulation of ERK1/2 phosphorylation was observed as a significant marker associated with AR. Importantly, targeting ERK inhibitors presents a potential therapeutic strategy for modulating key inflammatory response signaling pathways in the context of AR, although this finding is derived from preclinical mouse models and requires rigorous validation in human pediatric nasal mucosal tissues before any clinical translation can be considered. Collectively, these findings highlight that elucidating the molecular mechanisms underlying AR-induced nasal mucosal dysfunction in the mouse model may inform the novel therapeutic targets for pediatric allergy-related diseases. Overall, elucidating these mechanisms has substantial implications for developing targeted interventions aimed at mitigating inflammation associated with allergic rhinitis.

Animals↗
PubMed1995

A mouse model for testing the pathogenicity of equine herpes virus-1 strains.

A mouse model was developed for testing the pathogenicity of equine herpes virus-1 (EHV-1) strains. The model was validated with EHV-1 strains that are known to be of a low or high pathogenicity in horses. From all parameters tested, the safety index, which was calculated from the body weights of the mice after infection, proved to be the best predictive parameter. When this parameter was used, good and reliable correlations were found with the pathogenicity of the EHV-1 strains in horses. This method enabled the differentiation between the two experimental EHV-1 strains whose genetic backgrounds were supposedly equal.

Animals↗
PubMed1987

A mouse model of chronic pulmonary infection with Pseudomonas aeruginosa and Pseudomonas cepacia.

A mouse model of chronic pulmonary infection with either Pseudomonas aeruginosa or Pseudomonas cepacia was developed to compare bacteriologic and pathologic features of these infections. Experimental pneumonia was established in Swiss mice by transoral intratracheal inoculation of 10(3)-10(4) colony-forming units of mucoid P. aeruginosa or P. cepacia enmeshed in agarose beads. Unilateral infection with either strain was tolerated without morbidity. By 10 days postinoculation, the mean colony-forming units per infected lung was 3.8 X 10(5) for P. aeruginosa and 1.0 X 10(5) for P. cepacia. Bacterial counts remained stable through 21 days with no significant difference between organisms. Acute and chronic inflammatory histopathologic changes similar to many found in the lungs of cystic fibrosis patients were present in 95% of lung specimens. The changes occurred with both organisms but were more extensive with mucoid P. aeruginosa. This model represents an important tool for study of the contribution of complement, antibody, and adoptive transfer of T cell-mediated immunity to the pathogenesis of chronic pneumonia with Pseudomonas species, and represents the first successful model of chronic pulmonary infection with P. cepacia.

Animals↗
PubMed1987

Hepatic lipid abnormalities in a chemical/viral mouse model for Reye's syndrome.

We have examined hepatic lipid profiles in a mouse model for Reye's Syndrome (RS) in which young animals are exposed to nontoxic doses of an industrial pesticide emulsifier and subsequently are infected with sublethal doses of mouse-adapted human Influenza B (Lee) virus (FluB). The purpose of this study was to determine whether liver lipid content was altered in the mice, the time course of any changes, and whether lipid changes were consistent with liver pathology. Neonatal mice exposed dermally to the emulsifier, Toximul MP8 (Tox), had significantly elevated levels of hepatic cholesterol, with otherwise normal lipid composition. Subsequent inoculation of the mice with FluB significantly increased mortality rate. The combined Tox + FluB treatment had several significant effects on liver lipids, including a transient increase in phospholipid (PL) content, a reduction in neutral glycerides and persistently high cholesterol levels. Abnormalities in fatty acid profiles included an apparent elevation in medium chain fatty acids and increased ratios of PL arachidonic to docosahexaenoic acids. Histologically, there was no evidence of fat accumulation in the liver; however, hepatic mitochondria had severe structural abnormalities characteristic of RS. These studies demonstrate that chemical-dependent enhancement of viral virulence is associated with significant alterations of hepatic lipids. We believe that these abnormalities are related to mitochondrial structural damage in RS despite the absence of hepatic steatosis.

Animals↗
PubMed1990

Atherosclerosis mouse model induced by a high-cholesterol diet supplemented with beta-aminopropionitrile: effects of various anti-atherosclerotic agents on the biochemical parameters.

A mouse model of atherosclerosis was produced by feeding a 1.5% cholesterol diet with 0.4% beta-aminopropionitrile (BAPN) fumarate, a chemical lathyrogen, for 10 weeks, and the pharmacological sensitivity and specificity of this model were evaluated biochemically with various hypolipidemic drugs and calcium antagonists. Histological findings on this model showed typical angiolathyrism with foam cells in the media of the thoracic aorta. Uniform and marked accumulation of cholesterol, notably esterified cholesterol, in the aorta was observed, although it was much less in mice receiving a high-cholesterol diet or BAPN alone. The reduction in elastin contents in the aorta was a characteristic feature of this model. Clofibrate, cetaben and elastase tended to prevent the increase of cholesterol contents in the aorta, together with their significant hypocholesterolemic effects. Nifedipine, diltiazem and verapamil showed a slight preventive effect on the cholesterol accumulation and on the reduction of elastin content in the aorta without a cholesterol lowering effect in the serum. MgCl2 was more effective than other calcium antagonists and even had a hypocholesterolemic effect. The results indicate that this mouse atherosclerosis model may be usable for primary drug evaluation.

4-Aminobenzoic Acid↗
PubMed1993

Propagation of human papillomavirus type 11 in human xenografts using the severe combined immunodeficiency (SCID) mouse and comparison to the nude mouse model.

We report propagation of human papillomavirus (HPV) type 11 in human xenografts in the severe combined immunodeficiency (SCID) mouse and compare this new animal model for HPV infection to the previously established athymic nude mouse model. HPV-11-infected foreskin fragments grafted under the renal capsule of SCID mice formed large epithelial cysts that had the histologic and immunocytochemical features of HPV infection. This infection was successfully passaged to nude mice. Viral particles that reacted to an antibody directed to HPV-11 virions were identified from samples recovered from the SCID and nude mice. Viral DNA sequence analysis confirmed that the passaged virus was HPV-11. In a comparative experiment of the nude mouse and SCID mouse models, the latter produced HPV-11-infected xenografts that were larger and more often positive for HPV by immunocytochemistry and presence of viral mRNA than those propagated in the former model. Finally, we observed that growth of HPV-11-infected foreskin fragments in the SCID mouse model is not restricted to the kidney as in the nude mouse, but also can occur in the subcutis and the peritoneum.

Animals↗
PubMed1991

Towards a transgenic mouse model of sickle cell disease: hemoglobin SAD.

In order to obtain a transgenic mouse model of sickle cell disease, we have synthesized a novel human beta-globin gene, beta SAD, designed to increase the polymerization of the transgenic human hemoglobin S (Hb S) in vivo. beta SAD (beta S-Antilles-D Punjab) includes the beta 6Val substitution of the beta S chain, as well as two other mutations, Antilles (beta 23Ile) and D Punjab (beta 121Gln) each of which promotes the polymerization of Hb S in human. The beta SAD gene and the human alpha 2-globin gene, each linked to the beta-globin locus control region (LCR) were co-introduced into the mouse germ line. In one of the five transgenic lines obtained, SAD-1, red blood cells contained 19% human Hb SAD (alpha 2 human 1 beta 2SAD) and mouse-human hybrids in addition to mouse hemoglobin. Adult SAD-1 transgenic mice were not anemic but had some abnormal features of erythrocytes and slightly enlarged spleens. Their erythrocytes displayed sickling upon deoxygenation in vitro. SAD-1 neonates were anemic and many did not survive. In order to generate adult mice with a more severe sickle cell syndrome, crosses between the SAD progeny and homozygous for beta-thalassemic mice were performed. Hemoglobin SAD was increased to 26% in beta-thal/SAD-1 mice which exhibited: (i) abnormal erythrocytes with regard to shape and density; (ii) an enlarged spleen and a high reticulocyte count indicating an increased erythropoiesis; (iii) mortality upon hypoxia; (iv) polymerization of hemolysate similar to that obtained in human homozygous sickle cell disease; and (v) anemia and mortality during development.

Anemia, Sickle Cell↗
PubMed1987

Steroid receptors and human endometrial carcinoma: studies in a nude mouse model.

An experimental nude mouse system where human endometrial carcinomas of different histologic grade and steroid receptor characteristics can be grown and maintained under defined hormonal milieu by serial transplantation has been developed. Biologically and clinically important information on the role of steroid receptors in eliciting hormonal responses in these tumors has been obtained using this model. These results form the basis for designing and testing various treatment strategies for endometrial carcinomas of different histologic grade and receptor content.

Animals↗