SEARCH · PubMed Health

Results for “Models, Genetic”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources

PubMed2006

Cerebral vascular effects of angiotensin II: new insights from genetic models.

Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT1A receptors and Rho-kinase. Basilar arteries (baseline diameter approximately 130 microm) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by approximately 85% in mice deficient in expression of AT1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R+) and angiotensinogen (A+). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R+A+ mice (P<0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R+A+ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R+A+ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.

Angiotensin II↗

PubMed1993

Role of native disulfide bonds in the structure and activity of insulin-like growth factor 1: genetic models of protein-folding intermediates.

Insulin and insulin-related proteins contain three motif-specific disulfide bonds. Here we examine the role of these disulfide bonds in the folding and function of one family member, human insulin-like growth factor 1 (IGF-1). Analogues containing pariwise Cys-->Ser or Cys-->Ala substitutions were expressed in Escherichia coli, purified, and analyzed with respect to receptor-binding, solution structure, and thermodynamic stability. An analogue lacking all three disulfide bonds (designated des-Cys-IGF-1) is inactive and unfolded. Introduction of the [18-61] disulfide bond, previously shown to occur in an early intermediate in oxidative refolding [Miller, J. A., Owers-Narhi, L., Hua, Q. X., Rosenfeld, R., Arakawa, T., Rohde, M., Prestrelski, S., Lauren, S., S. Stoney, K. S., Tsai, L., & Weiss, M. A. (1993) Biochemistry (preceding paper in this issue)], results in a compact partially folded state with low but significant biological activity. Additional but incomplete structural organization and biological activity are observed following introduction of either the [6-48] or the [47-52] disulfide bonds. Native function, structure, and stability require the presence of all three disulfide bonds. These analogues provide genetic models of IGF-1 protein-folding intermediates. Their characterization suggests that bifurcation of the IGF-1 folding pathway reflects alternative late steps in the folding of a molten-globule intermediate.

Amino Acid Sequence↗

PubMed1995

Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus.

Resistance to the biological action of insulin in its target tissues is a cardinal feature of non-insulin-dependent diabetes mellitus. Protein-tyrosine phosphatases (PTPases) have been postulated to play a key role in the regulation of the insulin action pathway, especially in skeletal muscle, the major site of insulin-mediated glucose disposal in vivo. To evaluate whether changes in the activity and/or abundance of candidate skeletal muscle PTPases is associated with severe resistance to insulin in an animal model, we measured PTPase enzyme activity and PTPase protein level by immunoblotting in subcellular fractions of skeletal muscle in lean (+/?), insulin-resistant obese (fa/fa), and diabetic (ZDF/Drt-fa/fa) Zucker rats. Using a phosphotyrosylmyelin basic protein substrate, the solubilized-particulate fraction PTPase activity was increased by 65% and 74% (P < .05) and in vitro dephosphorylation of a recombinant rat insulin receptor kinase domain was increased by 104% and 114% in obese and diabetic animals, respectively (P < .01). These changes in PTPase activity were associated with an increase in specific immunoreactivity of leukocyte common antigen-related PTPase ([LAR] by 42% and 50%), PTPase 1B (by 61% and 69%), and the SHZ domain containing PTPase (SH-PTP2) (by 44% and 48%) in the solubilized-particulate fraction of obese and diabetic animals, respectively (P < .05). In diabetic muscle, increased SH-PTP2 abundance was also associated with a shift of SH-PTP2 to a plasma membrane component, which may have important consequences for the activation of this enzyme in the insulin-resistant state. These results provide evidence that specific PTPases play a role in the insulin resistance of this genetic model of obesity and non-insulin-dependent diabetes.

Animals↗

PubMed2002

Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease.

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation and of the number of vacuolated cells and better conservation of the mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the alpha3 subunit of Na,K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential, and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of alpha3 subunit Na,K-ATPase mRNA. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. However, because the gene mutation in Wobbler mice is still unknown, further studies are needed to unveil the action of PROG and the mechanism of neuronal death in this genetic model of neurodegeneration.

Animals↗

PubMed1992

Fitting genetic models to Carabelli trait data in South Australian twins.

This study aimed to clarify genetic and environmental contributions to Carabelli trait variation on permanent first molar teeth in a large sample of South Australian twins. Estimates of polychoric correlations were obtained between pairs of monozygous (MZ) and dizygous (DZ) twins for Carabelli data and various gene-environment models fitted by a weighted least-squares approach. The favored model included additive genetic effects together with both a general environmental component and an environmental effect specific to each side. An estimate of heritability around 90% indicated a very strong genetic contribution to observed variation. The pattern of correlations for MZ and DZ data suggested that further studies involving other types of relatives would be worthwhile for detection of possible non-additive genetic effects of dominance or epistasis.

Adolescent↗

PubMed1998

NER rat strain: a new type of genetic model in epilepsy research.

PURPOSE: We characterized and evaluated as an animal model of epilepsy NER, a new epileptic rat strain, which was developed by inbreeding rats with spontaneous tonic-clonic seizures in a stock of Crj:Wistar. METHODS: Animals were monitored through the inbreeding course, and video-EEGs were recorded selectively. External seizure-provoking stimuli were applied to NER and to a control parental strain. F1, F2, and backcross progenies were produced between NER and a nonepileptic unrelated strain. Pathologic study included hematoxylin-and-eosin (HE), Klüver-Barrera's, modified Bodian silver, and neo-Timm's staining. RESULTS: After the F9 generation, 94%-98% of NER exhibited spontaneous tonic-clonic convulsions, beginning with neck and forelimb clonus, wild jumping/running, opisthotonic posturing, and evolving to tonic, then clonic convulsion, followed by postictal flaccidity. Most seizure onsets occurred between 2-4 months of age, and the incidence was 0.45 +/- 0.21 seizures in 12 h. Ictal cortical and hippocampal EEGs were characterized by high-voltage spikes followed by diffuse spike-and-wave or polyspike-and-wave complexes. NER revealed seizure susceptibility to pentylenetetrazol, tossing, and transcorneal electroshock, but not to tactile, photic, or acoustic stimuli, or to transauricular electroshock. Mating experiments revealed that 0% (0/46) of the animals in F1, 25.5% (13/51) in F2, and 63.6% (56/88) in backcross progenies exhibited spontaneous tonic-clonic convulsions without sex difference. For all these epileptic traits, no pathologic changes were demonstrated in the CNS. CONCLUSIONS: NER frequently exhibited spontaneous convulsions, controlled by a major autosomal recessive gene for epilepsy, that are comparable to generalized tonic-clonic seizures in humans. This can serve as a new genetic model in epilepsy research.

Animals↗

PubMedDate not supplied

[Dog as a mammalian genetic model].

Up to recently, studies on dog genetics were rather scare notwithstanding the enormous potential that the canine model can offer in the study of the genotype/phenotype relationship and the analysis of the causes of many genetic diseases, with simple or complex inheritance, that affect dogs but also the human population. This potentiality is essentially due to the natural history of dogs whose domestication from wolves dated back 15,000 years, at least. All modern dogs originated from a limited number of female wolves from Eastern Asia. By applying a combination of selections and strong inbreeding practices, humans have created over 350 breeds, each of them corresponding to a genetic isolate and altogether offering a unique panel of polymorphism never encountered in any other mammals. In this review we summarized what makes dogs an unavoidable model. Contrary to the classical models like the two yeasts, nematode, fish, fly, mouse, or rat mainly used to understand the function of genes, dog with the creation across the centuries of numerous breeds offers a unique opportunity to study the role of their alleles. We report recent data on the construction of genomic maps and on the sequencing program of the dog genome launched by the National Institute of Health (NIH). To take fully advantage of the canine model, we advocate for the systematic construction of a rich canine single nucleotide polymorphisms (SNP) ressource to perform linkage desiquilibrium studies of normal or pathological traits as well as to get insight into the genetic diversity of the canine species.

Animals↗

PubMedDate not supplied

Adapting genetic regulatory models by genetic programming.

In this paper, we focus on the task of adapting genetic regulatory models based on gene expression data from microarrays. Our approach aims at automatic revision of qualitative regulatory models to improve their fit to expression data. We describe a type of regulatory model designed for this purpose, a method for predicting the quality of such models, and a method for adapting the models by means of genetic programming. We also report experimental results highlighting the ability of the methods to infer models on a number of artificial data sets. In closing, we contrast our results with those of alternative methods, after which we give some suggestions for future work.

Algorithms↗

PubMed2006

Mouse embryonic stem cells as a model genetic system to dissect and exploit the RNA interference machinery.

Conditional gene targeting is often a useful approach to elucidate the in vivo function of a gene. We use this approach to investigate the biological role of the RNA interference (RNAi) pathway in mammals. In addition, the RNAi machinery in mammalian cells can be exploited for gene knock-down experiments. In this chapter, we discuss the variety of experiments that can be performed using genetically engineered embryonic stem (ES) cells. ES cells provide a mammalian genetic system that is physiological, and tractable for mutagenesis and experimentation. This approach is economical and rapid, because it does not require production and breeding of genetically engineered mice.

Animals↗

PubMed1982

Genetic models of schizophrenia.

Multiple threshold models of inheritance are applied to a large sample of Franz Kallmann's (1938) pedigree data on schizophrenia. Paranoid and nonparanoid subtypes are represented in the models at different thresholds on a continuum of genetic-environmental liability. Single major locus and multifactorial-polygenic inheritance are ruled out as modes of transmission. These findings suggest that the paranoid-non-paranoid dichotomy cannot be used as a genetic threshold determinant in the population studied.

Gene Frequency↗

PubMed1999

Pattern formation and cell differentiation: trichomes in Arabidopsis as a genetic model system.

Arabidopsis trichomes are single-celled hairs that originate from epidermal cells and are distributed regularly on most aerial body parts. During the last decade, trichome formation in Arabidopsis has been established as a genetic and molecular model system to study various general developmental and cellular mechanisms. This review summarizes progress in the investigation of several aspects of trichome development: the spatial regulation of cell fate determination, the regulation of cell differentiation in response to exogenous signals and plant hormones, and the regulation of endoreplication, cell growth, and cell morphogenesis.

Arabidopsis↗

PubMed2005

Benefits from marker-assisted selection under an additive polygenic genetic model.

This study investigated, through stochastic computer simulation, the extra gains expected from marker-assisted selection (MAS) in an infinitesimal model with linkage. The trait under selection was assumed to be controlled by 2,000 loci of additive small effect and evenly distributed in c chromosomes of one Morgan each (and c = 5, 10, 20, or 30). This approach differs from previous studies on the benefits of MAS that have considered mixed inheritance models. Marker information was used together with pedigree information to compute the relationship matrix used in BLUP genetic evaluations. The MAS schemes were compared with schemes where genetic evaluations were performed using standard BLUP (i.e., the relationship matrix is obtained using pedigree information only). When the number of markers was large enough (approximately one marker every 10 cM), there were increases in the accuracy of selection with MAS, and this led to extra gains compared with standard BLUP for all genome sizes considered. The benefit from MAS increased over generations. At the last generation of selection (Generation 10), the response from MAS was 11, 9, 7, and 5% greater than with standard BLUP for genomes with 5, 10, 20, and 30 chromosomes, respectively. Thus, although small, gains from MAS were nonetheless detectable for genome sizes typical of livestock populations.

Animal Husbandry↗

PubMed2006

Mouse genetic model for antigen-induced airway manifestations of asthma.

Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic (RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.

Animals↗

PubMed2000

Drinks like a fish: zebra fish (Danio rerio) as a behavior genetic model to study alcohol effects.

Zebra fish may be an ideal vertebrate model system for numerous human diseases with which the genetics and biological mechanisms of the disease may be studied. Zebra fish has been successfully used in developmental genetics, and recently, neurobiologists have also started to study this species. A potentially interesting target disease amenable for analysis with zebra fish is drug addiction, e.g. alcoholism. Although genetic tools to manipulate the genome of zebra fish are available, appropriate phenotypical testing methods are often lacking. In this paper, we describe basic behavioral tests to investigate the acute effects of alcohol on zebra fish. These behavioral paradigms will be useful for the genetic and biological analysis of acute and chronic drug effects as well as addiction. In addition to presenting findings for the acute effects of alcohol, we briefly describe our strategy for generating and screening mutants. We hope that our pilot work will facilitate the future development of behavioral tests and the use of zebra fish in the genetic analysis of the biological effects of drugs of abuse.

Aggression↗

PubMed1998

Genetic control of blood infection levels in human malaria: evidence for a complex genetic model.

There is now accumulating evidence for the involvement of genetic factors in the control of immune response against malaria. These arguments come from numerous animal models, from population studies showing associations of red blood cell genetic defects as well as HLA antigens with severe malaria, and from familial studies including a recent segregation analysis, which led to detection of a major gene effect predisposing to high infection levels. The heterogeneity and complexity of this genetic control is one of the main findings of these previous studies, and probably a major cause of the difficulty in developing an effective malaria vaccine. A segregation analysis of blood infection levels is performed here in 44 pedigrees living in the tropical rain forest of southern Cameroon and exposed to high vectorial transmission intensity. The results confirm the existence of complex genetic factors controlling blood infection levels in human malaria but are not consistent with the parent-offspring transmission of a single Mendelian gene. This study also shows the dramatic effect of age on infection levels and its interaction with a putative major gene suggesting that genetic related differences are much more important in children than in adults. Further genetic studies focused on children may help to identify the nature of the genetic factors involved in the expression of human malaria, by means of linkage analyses using both familial information and genetic markers.

Adolescent↗

PubMed1973

The analysis of quantitative traits for simple genetic models from parental, F 1 and backcross data.

THE FOLLOWING MODELS ARE CONSIDERED FOR THE GENETIC DETERMINATION OF QUANTITATIVE TRAITS: segregation at one locus, at two linked loci, at any number of equal and additive unlinked loci, and at one major locus and an indefinite number of equal and additive loci. In each case an appropriate likelihood is given for data on parental, F(1) and backcross individuals, assuming that the environmental variation is normally distributed. Methods of testing and comparing the various models are presented, and methods are suggested for the simultaneous analysis of two or more traits.

Biometry↗

PubMed2001

Does accounting for mitochondrial genetic variation improve the fit of genetic models?

We describe a simple variance component model for estimating the effect of mitochondrial DNA (mtDNA) inheritance on quantitative trait variation. The model is applied to quantitative trait Q5 in the simulated general population data from Genetic Analysis Workshop (GAW) 12. Although the mitochondrial effect on Q5 is small (5.3%) and the power of the method to detect the effect is correspondingly low, analysis over the available population replicates demonstrates that the effect of maternal relatedness can be detected and estimated accurately.

Analysis of Variance↗

PubMed2006

Advances in behavioral genetics modeling using Mplus: applications of factor mixture modeling to twin data.

This article discusses new latent variable techniques developed by the authors. As an illustration, a new factor mixture model is applied to the monozygotic-dizygotic twin analysis of binary items measuring alcohol-use disorder. In this model, heritability is simultaneously studied with respect to latent class membership and within-class severity dimensions. Different latent classes of individuals are allowed to have different heritability for the severity dimensions. The factor mixture approach appears to have great potential for the genetic analyses of heterogeneous populations. Generalizations for longitudinal data are also outlined.

Adult↗