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V Bílá

Publications and source records attributed to V Bílá.

At least 19 recordsLinked to original sources
PubMed2004

Genetic analysis of "metabolic syndrome" in the spontaneously hypertensive rat.

In the current review, we summarize results of genetic analyses of "metabolic syndrome" in the spontaneously hypertensive rat (SHR). These results include (1) linkage analyses in the HXB/BXH recombinant inbred (RI) strains derived from SHR and Brown Norway (BN-Lx) strains which revealed quantitative trait loci (QTL) for hemodynamic and metabolic traits on several chromosomes, (2) genetic isolation of these putative QTL within differential chromosome segments of SHR.BN congenic strains, (3) detailed mapping of these QTL within limited chromosome segments of SHR.BN congenic sublines, (4) sequencing of selected positional candidate genes which revealed important mutations in the Cd36 and Srebp1 SHR genes, (5) functional tests of these candidate genes in SHR transgenic lines, and (6) integrated gene expression profiling and linkage mapping in RI strains which will be used to identify co-regulated genes and to determine co-segregation of transcriptional profiles with physiological and pathophysiological phenotypes.

Animals↗
PubMed1999

Mapping of quantitative trait loci for seminal vesicle mass and litter size to rat chromosome 8.

The spontaneously hypertensive rat (SHR) and the Brown Norway (BN) rat differ significantly in litter size (7.6 versus 4.5 pups). In the HXB and BXH sets of recombinant inbred (RI) strains derived from SHR and BN rats, heritability of litter size and of selected male reproductive parameters such as sperm production, sperm count, sperm morphology and motility, and the mass of the testis, epididymides, and seminal vesicles were estimated and a search was undertaken for quantitative trait loci (QTL) associated with these phenotypes. The mass of seminal vesicles was significantly associated with a QTL near the D8Cebr204S21 marker on chromosome 8 (LOD score = 4.1, P = 0.00001); this QTL was responsible for 46% of the genetic variability of the trait. The same gene marker on chromosome 8 also showed a suggestive association with the litter size. Litter size was significantly correlated with the mass of seminal vesicles (r = 0.58, P = 0.003). These findings indicate that the variability in litter size among RI strains may be due in part to differences in the mass of seminal vesicles and it is possible that both mass of seminal vesicles and litter size are determined by a pleiotropic effect of the same QTL on rat chromosome 8.

Animals↗
PubMed1999

Genetic analysis of the rat hypodactylous mutation.

Autosomal recessive rat hypodactylous mutation Hd leads in homozygous condition to reductive changes of the digital arch of all feet. There is a variable preaxial reduction of the number of fingers in both sexes. Moreover, homozygous males are sterile. Testes of homozygous Hd/Hd and +/Hd adult rats were examined in the light and electron microscopes. Spatial organization of stages of the spermatogenetic cycle was not confirmed in Hd/Hd testes comparing with +/Hd males. Significant decrease in the number of germ cells in seminiferous tubules of Hd/Hd testes was accompanied with loosening and vacuolization of the seminiferous epithelium. The assignment of the Hd locus to RNO10 excluded the suspected homology between rat and mouse Hd mutations. More precise mapping using microsatellite markers revealed close linkage of the Hd locus with the D1OMit8 marker defining Syb2 gene coding for synaptobrevin 2. A chromosomal segment of RNO10 carrying Hd and Syb genes is being incrossed onto BN and SHR inbred strains in order to examine the modifying influences of different genetic backgrounds.

Abnormalities, Multiple↗
PubMed1999

Hematocrit and hemoglobin values are negatively correlated with insulin resistance in spontaneous hypertension.

It has been recently reported that increased hematocrit and hemoglobin values often accompany insulin resistance and compensatory hyperinsulinemia in humans. In the current study, we analyzed the relationship between hematocrit/hemoglobin on the one hand and insulin resistance, dyslipidemia, and hypertension on the other hand in HXB/BXH recombinant inbred (RI) strains derived from the spontaneously hypertensive rat (SHR) and the Brown Norway (BN) rat. The SHR progenitor strain had a significantly increased hematocrit values and it was also hypertensive and insulin-resistant when compared with the BN progenitor. The distribution of hematocrit and hemoglobin values among RI strains was continuous, suggesting a polygenic mode of inheritance. Analysis of RI strains revealed that hemoglobin was negatively correlated with insulin and insulin/glucose ratio, and that hematocrit was negatively correlated with insulin-stimulated glucose uptake in isolated adipocytes. There was no relationship between hematological parameters and blood pressure or lipid phenotypes in RI strains. The findings of the current study suggest that hematocrit and hemoglobin values might be added to the clustering variables related to the insulin resistance syndrome in the SHR strain.

Animals↗
PubMed1998

A genetic and correlation analysis of liver cholesterol concentration in rat recombinant inbred strains fed a high cholesterol diet.

Liver cholesterol concentration in rats fed a high cholesterol diet, is under genetic control which is supported by significant differences observed among inbred strains. For instance, the Brown Norway (BN-Lx/Cub) rat developed a twofold higher liver cholesterol concentration than the spontaneously hypertensive rat (SHR/Ola). In the current study, we used 30 recombinant inbred (RI) strains, derived from BN-Lx and SHR progenitors, to locate quantitative trait loci (QTL) that are responsible for differences in liver cholesterol concentrations between the BN-Lx and SHR strains. The heritability of liver cholesterol was estimated to be 0.55 and a significant association was detected between concentration of liver cholesterol and the D10Cebrp1016s2 marker on chromosome 10 (lod score = 3.3); this putative QTL was responsible for nearly 64% of additive genetic variability and thus represents a major genetic determinant of liver cholesterol concentration. Liver cholesterol concentrations significantly correlated with intermediate density lipoprotein (IDL) cholesterol levels.

Animals↗
PubMed1997

Genotoxicity of purine acyclic nucleotide analogs.

The genotoxic and embryotoxic effects of phosphonomethoxyalkylpurines, a new group of antiviral agents, decrease in the following order: PMEG > PMEthioG > PMEDAP > PMEA > (R)-PMPDAP = (R)-PMPA. Results of the present study are fully consistent with the previously found efficacy of their diphosphates to inhibit the replicative DNA polymerases. The marked genotoxicity of PMEG and PMEthioG is comparable to that of mitomycin C, whereas the moderate genotoxicity of PMEA is comparable to that of AZT. (R)-PMPDAP and (R)-PMPA did not induce any structural aberrations of chromosomes under the experimental conditions.

Adenine↗
PubMed1996

Quantitative trait loci influencing cholesterol and phospholipid phenotypes map to chromosomes that contain genes regulating blood pressure in the spontaneously hypertensive rat.

The frequent coincidence of hypertension and dyslipidemia suggests that related genetic factors might underlie these common risk factors for cardiovascular disease. To investigate whether quantitative trait loci (QTLs) regulating lipid levels map to chromosomes known to contain genes regulating blood pressure, we used a genome scanning approach to map QTLs influencing cholesterol and phospholipid phenotypes in a large set of recombinant inbred strains and in congenic strains derived from the spontaneously hypertensive rat and normotensive Brown-Norway (BN.Lx) rat fed normal and high cholesterol diets. QTLs regulating lipid phenotypes were mapped by scanning the genome with 534 genetic markers. A significant relationship (P < 0.00006) was found between basal HDL2 cholesterol levels and the D19Mit2 marker on chromosome 19. Analysis of congenic strains of spontaneously hypertensive rat indicated that QTLs regulating postdietary lipid phenotypes exist also on chromosomes 8 and 20. Previous studies in the recombinant inbred and congenic strains have demonstrated the presence of blood pressure regulatory genes in corresponding segments of chromosomes 8, 19, and 20. These findings provide support for the hypothesis that blood pressure and certain lipid subfractions can be modulated by linked genes or perhaps even the same genes.

Animals↗
PubMed1996

A genetic linkage map of the rat derived from recombinant inbred strains.

We have constructed a genetic linkage map in the rat by analyzing the strain distribution patterns of 500 genetic markers in a large set of recombinant inbred strains derived from the spontaneously hypertensive rat and the Brown-Norway rat (HXB and BXH recombinant inbred strains). 454 of the markers could be assigned to specific chromosomes, and the amount of genome covered by the mapped markers was estimated to be 1151 centimorgans. By including a variety of morphologic, biochemical, immunogenetic, and molecular markers, the current map integrates and extends existing linkage data and should facilitate rat gene mapping and genetic studies of hypertension and other complex phenotypes of interest in the HXB and BXH recombinant inbred strains.

Animals↗
PubMed1996

Recombinant inbred and congenic strains for mapping of genes that are responsible for spontaneous hypertension and other risk factors of cardiovascular disease.

The spontaneously hypertensive rat (SHR) is the most widely used animal model of human essential hypertension. In the SHR strain, as in humans, the high blood pressure is determined multifactorially. Analysis of genetically segregating populations, derived from SHR and normotensive inbred strains, enabled localization of quantitative trait loci (QTLs) responsible for blood pressure regulation on several rat chromosomes. Analysis of specialized strains, congenic and recombinant inbred (RI) strains, helped to analyze some of these mapping results in detail: (1) analysis of congenic strains provided definitive evidence for the presence of blood pressure regulatory genes on chromosomes 8 and 13 and will enable mapping of responsible genes to limited segments of differential chromosomes, (2) the RI strains were shown to be especially useful for genome scanning studies of complex traits and for correlation analysis of blood pressure and other risk factors of cardiovascular disease such as cardiac hypertrophy, dyslipidemia, and insulin resistance.

Animals↗
PubMed1996

Recombinant inbred and congenic strains of the rat for genetic analysis of limb morphogenesis.

Recombinant inbred (RI) and congenic strains carrying the polydactyly-luxate syndrome (PLS) provide an experimental model for the analysis of polygenic control of limb development. PLS is determined by a major gene Lx whose phenotypic expression is strongly influenced by the genetic background upon which it operates. The morphometric analysis of the skeleton of front and hind legs has been carried out. The morphotypes of PLS in RI strains exhibit a continuous variability and transgressive variation compared to BN.Lx and SHR.Lx morphotypes, which strongly indicates the polygenic effects on PLS manifestation. Quantitative trait loci (QTL) were searched for through correlation of genetic markers and morphometric traits. The association analysis revealed statistically significant correlations (P < 0.0003) of morphometric traits with two markers on chromosome 4 (Il6 and A2m) associated with the number of front feet and hind feet phalanges, respectively, one marker on chromosome 7 (D7Mit17) associated with the tibia length, and the somatostatin gene on chromosome 11 associated with the number of front feet phalanges. In addition, suggestive associations of morphometric traits with markers on further nine chromosomes have been found (correlation coefficients ranging from 0.5 to 0.6). The verification of all these findings is in progress by means of double congenic strains which, in addition to the Lx gene, carry differential chromosome segments with putative modifiers.

Animals↗
PubMed1996

The teratogenic action of retinoic acid in rat congenic and recombinant inbred strains.

The teratogenic effect of all-trans retinoic acid (RA) was tested in the system of congenic and recombinant inbred (RI) strains of the laboratory rat carrying the mutant Lx allele which determines the polydactyly-luxate syndrome. It was demonstrated that the teratogenic effect of RA is influenced by both the genotype at the Lx locus and the modifying genes. The dose of 100 mg/kg administered by gavage on day 11 of pregnancy induced a statistically significant incidence of preaxial polydactyly in hind limbs of LEW/BN, +/Lx foetuses heterozygous in the mutant allele, whereas no specific limb defects were noted in foetuses LEW/BN, +/+ without the mutant allele. In foetuses homozygous in the mutant allele LEW/BN, Lx/Lx and SHR/BXH2, Lx/Lx, RA conversely induced a significant reduction in the number of toes on the preaxial side of hind limbs and a reduction of the zeugopodium, mostly the tibia. Reduction changes were more marked in SHR/BXH2, Lx/Lx foetuses, in which the tibia was entirely missing and sirenomelia was found. The foetuses in this group have in their genetic background a combination of modifiers that are responsible for oligodactyly and tibial hemimelia in the BXH2 strain. On the basis of continuing mapping of the rat genome, the testing of RA in the system of RI and congenic strains will be utilized for identification of so far hypothetical genes involved in morphogenesis.

Animals↗
PubMed1994

Evidence for teratogenicity of thalidomide using congenic and recombinant inbred rat strains.

Teratogenic properties of thalidomide were tested in two systems of laboratory rat strains carrying the mutant lx allele that determines the polydactyly-luxate syndrome. In agreement with our previous experiments, we have confirmed that the response of foetuses basically depends on their genotype. Foetuses of LEW/BN, +/+ genotype remained unaffected following 500 or 3 x 500 mg/kg thalidomide doses (43 and 56 foetuses, respectively). In LEW/BN, +/lx foetuses these doses elicited 24% and 87% hind feet polydactyly (14/59 and 53/61 foetuses, respectively), which was highly significant when compared with 84 vehiculum-treated and 235 untreated controls (P < 0.001). However, in 48 SHR/RI 2, lx/lx foetuses both pairs of limbs were affected in an opposite way after the 500 mg/kg thalidomide dose: hind feet oligodactyly (94/96 limbs) and increased front feet polydactyly occurred (in comparison with 70 controls, P < 0.001). The mutant lx allele as well as modifying genes are involved in the response to thalidomide.

Abnormalities, Drug-Induced↗