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
Coan, P. M. - Hummel, O. - Diaz, A. G. - Barrier, M. - Alfazema, N. - Norsworthy, P. J. - Pravenec, Michal - Petretto, E. - Hübner, N. - Aitman, T. J.
Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat
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Disease Models & Mechanisms. 2017, roč. 10, 3, p. 297-306
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IF = 4.691
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Kurtz, T. W. - DiCarlo, S. E. - Pravenec, Michal - Morris Jr., R. C.
An Appraisal of Methods Recently Recommended for Testing Salt Sensitivity of Blood Pressure
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Journal of the American Heart Association. 2017, roč. 6, 4, článku e005653
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IF = 4.863
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Neckář, Jan - Svatoňová, Anna - Weissová, Romana - Drahota, Zdeněk - Zajíčková, Pavlína - Brabcová, I. - Kolář, D. - Alánová, Petra - Vašinová, Jana - Šilhavý, Jan - Hlaváčková, Markéta - Tauchmannová, Kateřina - Milerová, Marie - Ošťádal, Bohuslav - Červenka, L. - Žurmanová, Jitka - Kalous, M. - Nováková, Olga - Novotný, J. - Pravenec, Michal - Kolář, František
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Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats
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Clinical science. 2017, roč. 131, 9, p. 865-881
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IF = 4.936
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Liška, F. - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šilhavý, Jan - Šimáková, Miroslava - Strnad, Hynek - Trnovská, J. - Škop, V. - Kazdová, L. - Starker, C.G. - Voytas, D.F. - Izsvák, Z. - Mancini, M. - Šeda, O. - Křen, V. - Pravenec, Michal
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Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat
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Hypertension. 2017, roč. 69, 6, p. 1084-1091
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IF = 6.857
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Liška, F. - Chylíková, B. - Janků, M. - Šeda, Ondřej - Vernerová, Z. - Pravenec, Michal - Křen, Vladimír
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Splicing mutation in Sbf1 causes nonsyndromic male infertility in the rat
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Reproduction. 2016, roč. 152, 3, p. 215-223
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IF = 3.100
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Abdelmagid, N. - Bereczky-Veress, B. - Atanur, S. - Musilová, Alena - Zídek, Václav - Saba, L. - Warnecke, A. - Khademi, M. - Studahl, M. - Aurelius, E. - Hjalmarsson, A. - Garcia-Dias, A. - Denis, C. V. - Bergström, N. - Sköldenberg, B. - Kockum, I. - Aitman, T. - Hübner, N. - Olsson, T. - Pravenec, Michal - Diez, M.
Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis
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PLoS ONE. 2016, roč. 11, 5, e0155832
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IF = 2.806
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Malínská, H. - Oliyarnyk, O. - Škop, V. - Šilhavý, Jan - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šimáková, Miroslava - Strnad, Hynek - Kazdová, L. - Pravenec, Michal
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Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein
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PLoS ONE. 2016, roč. 11, 3, e0150924
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IF = 2.806
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Šedová, Lucie - Pravenec, Michal - Křenová, D. - Kazdová, L. - Zídek, Václav - Krupková, M. - Liška, F. - Křen, Vladimír - Šeda, Ondřej
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Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model
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PLoS ONE. 2016, roč. 11, 3, článku e0152708
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IF = 2.806
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Liška, F. - Peterková, Renata - Peterka, Miroslav - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šilhavý, Jan - Šimáková, Miroslava - Křen, Vladimír - Starker, C.G. - Voytas, D.F. - Izsvák, Z. - Pravenec, Michal
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Targeting of the Plzf Gene in the Rat by Transcription Activator-Like Effector Nuclease Results in Caudal Regression Syndrome in Spontaneously Hypertensive Rats
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PLoS ONE. 2016, roč. 11, 10, e0164206
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IF = 2.806
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Škop, V. - Trnovská, J. - Oliyarnyk, O. - Marková, I. - Malínská, H. - Kazdová, L. - Zídek, Václav - Landa, Vladimír - Mlejnek, Petr - Šimáková, Miroslava - Kůdela, M. - Pravenec, Michal - Šilhavý, Jan
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Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein
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Physiological Research. 2016, roč. 65, 6, p. 891-899
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IF = 1.461
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