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Laboratory of Genetics of Model Diseases

Laboratory of Genetics of Model Diseases

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

Linkage and correlation analyses of intermediary phenotypes in the SHR for identification of candidate genes regulating pathophysiological traits

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.  More

In vivo functional analyses of candidate genes for hemodynamic and metabolic traits

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.  More

Publications

Šilhavý; Jan - Mlejnek; Petr - Šimáková; Miroslava - Liška; František - Kubovčiak; Jan - Sticová; E. - Pravenec; Michal . Sodium Accumulation and Blood Capillary Rarefaction in the Skin Predispose Spontaneously Hypertensive Rats to Salt Sensitive Hypertension . Biomedicines. 2022; 10(2)); 376 . IF = 4.757 [ASEP] [ doi ]
Senko; A. N. - Overall; R. W. - Šilhavý; Jan - Mlejnek; Petr - Malínská; H. - Hüttl; M. - Marková; I. - Fabel; K. S. - Lu; L. - Stuchlík; Aleš - Williams; R. W. - Pravenec; Michal - Kempermann; G. Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose . PLoS Genetics. 2022; 18(4)); e1009638 . IF = 6.200 [ASEP] [ doi ]
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 . Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat . Biomedicines. 2022; 10(2)); 276 . IF = 4.757 [ASEP] [ doi ]
Lusk; R. - Hoffman; P.L. - Mahaffey; S. - Rosean; S. - Smith; H. - Šilhavý; Jan - Pravenec; Michal - Tabakoff; B. - Saba; L. M. Beyond Genes: Inclusion of Alternative Splicing and Alternative Polyadenylation to Assess the Genetic Architecture of Predisposition to Voluntary Alcohol Consumption in Brain of the HXB/BXH Recombinant Inbred Rat Panel . Frontiers in genetics. 2022; 13(Mar 15)); 821026 . IF = 4.772 [ASEP] [ doi ]
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? . Hypertension. 2022; 79(4); 809-812 . IF = 9.897 [ASEP] [ doi ]
Kurtz; T. W. - Pravenec; Michal - DiCarlo; S. E. Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension . Clinical science. 2022; 136(8); 599-620 . IF = 6.876 [ASEP] [ doi ]
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 . Life Science Alliance. 2022; 5(4)); e202101234 . IF = 5.781 [ASEP] [ doi ]
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 . Genome Biology. 2021; 22(1)); 191 . IF = 17.906 [ASEP] [ doi ]
Pravenec; Michal - Šilhavý; Jan - Mlejnek; Petr - Šimáková; Miroslava - Mráček; Tomáš - Pecinová; Alena - Tauchmannová; Kateřina - Hüttl; M. - Malínská; H. - Kazdová; L. - Neckář; Jan - Kolář; František - Žurmanová; J. - Novotný; J. - Houštěk; Josef . Conplastic strains for identification of retrograde effects of mitochondrial dna variation on cardiometabolic traits in the spontaneously hypertensive rat . Physiological Research. 2021; 70(Suppl.4); S471-S481 . IF = 2.139 [ASEP] [ doi ]
Neckář; Jan - Alánová; Petra - Olejníčková; Veronika - Papoušek; František - Hejnová; L. - Šilhavý; Jan - Behuliak; Michal - Bencze; Michal - Hrdlička; Jaroslav - Vecka; M. - Jarkovská; D. - Švíglerová; J. - Mistrová; E. - Štengl; M. - Novotný; J. - Ošťádal; Bohuslav - Pravenec; Michal - Kolář; František . Excess ischemic tachyarrhythmias trigger protection infarction in rats . Clinical science. 2021; 135(17); 2143-2163 . IF = 6.876 [ASEP] [ doi ]
Mihola; Ondřej - Landa; Vladimír - Pratto; F. - Brick; K. - Kobets; Tetyana - Kusari; Fitore - Gašić; Srdjan - Smagulova; F. - Grey; C. - Flachs; Petr - Gergelits; Václav - Třešňák; Karel - Šilhavý; Jan - Mlejnek; Petr - Camerini-Otero; R.D. - Pravenec; Michal - Petukhova; G.V. - Trachtulec; Zdeněk . Rat PRDM9 shapes recombination landscapes; duration of meiosis; gametogenesis; and age of fertility . BMC BIOLOGY. 2021; 19(1)); 86 . IF = 7.364 [ASEP] [ doi ]
Kurtz; T. W. - DiCarlo; S. E. - Pravenec; Michal - Morris Jr.; R. C. No evidence of racial disparities in blood pressure salt sensitivity when potassium intake exceeds levels recommended in the US dietary guidelines . American Journal of Physiology-Heart and Circulatory Physiology. 2021; 320(5); H1903-H1918 . IF = 5.125 [ASEP] [ doi ]
Křížová; J. - Hůlková; M. - Čapek; V. - Mlejnek; Petr - Šilhavý; Jan - Tesařová; M. - Zeman; J. - Hansíková; H. Microarray and qPCR Analysis of Mitochondrial Metabolism Activation during Prenatal and Early Postnatal Development in Rats and Humans with Emphasis on CoQ(10) Biosynthesis . BIOLOGY-BASEL. 2021; 10(5)); 418 . IF = 5.168 [ASEP] [ doi ]
Krijt; J. - Sokolová; J. - Šilhavý; Jan - Mlejnek; Petr - Kubovčiak; Jan - Liška; František - Malínská; H. - Hüttl; M. - Marková; I. - Křížková; M. - Stipanuk; M. H. - Křížek; T. - Ditroi; T. - Nagy; P. - Kožich; V. - Pravenec; Michal . High Cysteine Diet Reduces Insulin Resistance in SHR-CRP Rats . Physiological Research. 2021; 70(5); 687-700 . IF = 2.139 [ASEP] [ doi ]
Junková; K. - Mirchi; L. F. - Chylíková; B. - Janků; M. - Šilhavý; Jan - Hüttl; M. - Marková; I. - Miklánková; D. - Včelák; J. - Malínská; H. - Pravenec; Michal - Šeda; O. - Liška; František . Hepatic Transcriptome Profiling Reveals Lack of Acsm3 Expression in Polydactylous Rats with High-Fat Diet-Induced Hypertriglyceridemia and Visceral Fat Accumulation . Nutrients. 2021; 13(5)); 1462 . IF = 6.706 [ASEP] [ doi ]

People

Ing. Michal Pravenec, DrSc.

Head of the Laboratory

Ing. Jan Šilhavý, PhD.
Deputy Head of the Laboratory

Ing. Miroslava Šimáková, PhD.

Senior Researcher

Ing. Petr Mlejnek, PhD.
Senior Researcher

doc. MUDr. František Liška, PhD.

Senior Researcher

  Ing. Magdalena Melčová
PhD Student
Alena Musilová
Technician