Metabolic syndrome is a cluster of several risk factors for type 2 diabetes and cardiovascular disease, including obesity, hypertension, insulin resistance, and dyslipidemia. These pathological conditions are determined multifactorially by many genes and their interactions with environmental effects. Genome wide association studies (GWAS) in humans which are based on the “common variants – common diseases“ hypothesis identified only a minor proportion of the total heritability of complex traits so far.
Statistically significant variants (SNPs – single nucleotide polymorphisms) are typically associated with a miniscule phenotypic variability without meaningful clinical effects. Studies in animal models of human complex diseases can provide a useful alternative. Experiments with rat models can control for both genetic background and environmental effects as well as enable genetic manipulation of experimental animals. The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and associated metabolic disturbances typical for metabolic syndrome. Although it cannot be expected that the individual predisposing genes themselves might be conserved between rats and humans, it is likely that the networks and pathways of genes leading to disease susceptibility will be conserved across species. Therefore, identification of the networks and pathways of genes underlying the cellular pathology of disease phenotypes in the rat could provide insight into the pathogenesis and treatment of the corresponding human diseases.
Our research is focused on these projects:
- Identification of genes that regulate hemodynamic and metabolic traits in the SHR.
- Identification of new genes coding for mitochondrial proteins and their role in the pathogenesis of metabolic syndrome.
- Derivation of new animal models using highly effective methods for transgenesis and gene targeting.
- Study of the role of inflammatory processes and oxidative stress in the pathogenesis of metabolic syndrome and possibility of pharmacologic interventions.
Current grant support.
Projects
Recently, new highly efficient techniques become available for derivation of transgenic or knockout rats for in vivo functional studies of candidate genes for QTL, for analyses of genes with unknown function or for derivation of new rat models of human diseases.
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For genetic dissection of complex pathophysiological traits in recombinant inbred (RI) strains, it is possible to take the advantage of accumulated genotypes and intermediary phenotypes. Intermediate phenotypes have simpler genetic architectures and can be used for connecting variabilty at the DNA level with complex pathophysiological traits. Abundance of mRNA (transcriptome), proteins (proteome), metabolites (metabolome), etc. are the most widely used intermediary phenotypes.
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Candidate genes for pathophysiological traits, identified by linkage and correlation analyses with intermediary phenotypes and by their sequencing, are tested by in vivo functional analysis in transgenic rescue or knockout experiments with the aim to identify quantitative trait loci at the molecular level and analyze responsible pathophysiological mechanisms.
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We plan to identify genetic determinants of the mitochondrial proteome in relation to important complex disease traits in the rat and thereby improve understanding of the pathogenetic role of mitochondria in common clinical disorders.
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Publications
Šilhavý; Jan - Mlejnek; Petr - Šimáková; Miroslava - Liška; František - Kubovčiak; Jan - Sticová; E. - Pravenec; Michal
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Sodium Accumulation and Blood Capillary Rarefaction in the Skin Predispose Spontaneously Hypertensive Rats to Salt Sensitive Hypertension
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Biomedicines. 2022; 10(2)); 376
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IF = 6.081
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Marković; Aleksandra - Tauchmannová; Kateřina - Šimáková; Miroslava - Mlejnek; Petr - Kaplanová; Vilma - Pecina; Petr - Pecinová; Alena - Papoušek; František - Liška; František - Šilhavý; Jan - Mikešová; Jana - Neckář; Jan - Houštěk; Josef - Pravenec; Michal - Mráček; Tomáš
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Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat
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Biomedicines. 2022; 10(2)); 276
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IF = 6.081
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Kurtz; T. W. - Pravenec; Michal - DiCarlo; S. E.
Will Food and Drug Administration Guidance to Reduce the Salt Content of Processed Foods Reduce Salt Intake and Save Lives?
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Hypertension. 2022; 79(4); 809-812
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IF = 10.190
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Dahale; S. - Ruiz-Orera; J. - Šilhavý; Jan - Hübner; N. - van Heesch; S. - Pravenec; Michal - Atanur; S. S.
Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension
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Life Science Alliance. 2022; 5(4)); e202101234
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IF = 4.591
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Witte; F. - Ruiz-Orera; J. - Mattioli; C. C. - Blachut; S. - Adami; E. - Schulz; J. F. - Schneider-Lunitz; V. - Hummel; O. - Patone; G. - Mücke; M. B. - Šilhavý; Jan - Heinig; M. - Bottolo; L. - Sanchis; D. - Vingron; M. - Chekulaeva; M. - Pravenec; Michal - Hubner; N. - van Heesch; S.
A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion
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Genome Biology. 2021; 22(1)); 191
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IF = 13.583
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