Intranet Čeština

Genetics of Model Diseases

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

Trnovská, J. - Šilhavý, Jan - Zídek, Václav - Šimáková, Miroslava - Mlejnek, Petr - Landa, Vladimír - Eigner, Sebastian - Eigner-Henke, Kateřina - Škop, V. - Oliyarnyk, O. - Kazdová, L. - Mráček, Tomáš - Houštěk, Josef - Pravenec, Michal . Gender-related effects on substrate utilization and metabolic adaptation in hairless spontaneously hypertensive rat . Physiological Research. 2015, Vol. 64, 1, p. 51-60 . IF = 1.293 [ASEP]
Šilhavý, Jan - Zídek, Václav - Landa, Vladimír - Šimáková, Miroslava - Mlejnek, Petr - Oliyarnyk, O. - Malínská, H. - Kazdová, L. - Mancini, M. - Pravenec, Michal . Rosuvastatin ameliorates inflammation, renal fat accumulation, and kidney injury in transgenic spontaneously hypertensive rats expressing human C-reactive protein . Physiological Research. 2015, Vol. 64, 3, p. 295-301 . IF = 1.293 [ASEP]
Schafer, S. - Adami, E. - Heinig, M. - Rodrigues, K. E. C. - Kreuchwig, F. - Šilhavý, Jan - van Heesch, S. - Simaite, D. - Rajewsky, N. - Cuppen, E. - Pravenec, Michal - Vingron, M. - Cook, S. A. - Hubner, N. Translational regulation shapes the molecular landscape of complex disease phenotypes . Nature Communications. 2015, Vol. 6, -, p. 7200 . IF = 11.470 [ASEP] [ doi ]
Kurtz, T. W. - Dominiczak, A. F. - DiCarlo, S. E. - Pravenec, Michal - Morris Jr., R. C. Molecular-Based Mechanisms of Mendelian Forms of Salt-Dependent Hypertension Questioning the Prevailing Theory . Hypertension. 2015, Vol. 65, 5, p. 932-941 . IF = 6.480 [ASEP] [ doi ]
Heinig, M. - Colomé-Tatché, M. - Taudt, A. - Rintisch, C. - Schafer, S. - Pravenec, Michal - Hubner, N. - Vingron, M. - Johannes, F. histoneHMM: Differential analysis of histone modifications with broad genomic footprints . B M C Bioinformatics. 2015, Vol. 16, Feb 22, p. 60 . IF = 2.576 [ASEP] [ doi ]

Contacts

Institute of Physiology AS CR, v.v.i.
Department of Genetics of Model Diseases

Vídeňská 1083
14220 Prague 4
Czech Republic
tel. +420 241 062 297
fax. +420 241 062 488
 

pravenec@fgu.cas.cz

People

Ing. Michal Pravenec, DrSc.

head of the department

Ing. Václav Zídek, CSc.

senior researcher

Ing. Vladimír Landa, CSc.
senior researcher

Ing. Miroslava Šimáková, PhD.

senior researcher

Ing. Petr Mlejnek, PhD.
senior researcher
Ing. Jan Šilhavý, PhD.
senior researcher
  Ing. Petr Svoboda
PhD student
Alena Musilová
technician

© 2014 INSTITUTE OF PHYSIOLOGY CAS