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INSTITUTE OF PHYSIOLOGY CAS

Cutting-edge science for health

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

Tan, A. L. M. - Langley, S. R. - Tan, Ch. F. - Chai, J. F. - Khoo, CH. M. - Leow, M. K.-S. - Khoo, E. Y. H. - Moreno-Moral, A. - Pravenec, Michal - Rotival, M. - Sadananthan, S. A. - Velan, S. S. - Venkataraman, K. - Chong, Y. S. - Lee, Y. S. - Sim, X. - Stunkel, W. - Liu, M. H. - Tai, E. S. - Petretto, E. Ethnicity-Specific Skeletal Muscle Transcriptional Signatures and Their Relevance to Insulin Resistance in Singapore . Journal of Clinical Endocrinology and Metabolism 2019, 104(2), 465-486 . IF = 5.605 [ASEP] [ doi ]
Nedvědová, I. - Kolář, D. - Neckář, Jan - Kalous, M. - Pravenec, Michal - Šilhavý, Jan - Korenková, Vlasta - Kolář, František - Žurmanová, J.M. Cardioprotective Regimen of Adaptation to Chronic Hypoxia Diversely Alters Myocardial Gene Expression in SHR and SHR-mt(BN) Conplastic Rat Strains . Frontiers in Endocrinology 2019, 9(Jan 22)), 809 . IF = 3.634 [ASEP] [ doi ]
Morris Jr., R. C. - Pravenec, Michal - Šilhavý, Jan - DiCarlo, S. E. - Kurtz, T. W. Small Amounts of Inorganic Nitrate or Beetroot Provide Substantial Protection From Salt-Induced Increases in Blood Pressure . Hypertension 2019, 73(5), 1042-1048 . IF = 7.017 [ASEP] [ doi ]
Kurtz, T. W. - DiCarlo, S. E. - Pravenec, Michal - Morris, R. C. Changing views on the common physiologic abnormality that mediates salt sensitivity and initiation of salt-induced hypertension: Japanese research underpinning the vasodysfunction theory of salt sensitivity . Hypertension Research 2019, 42(1), 6-18 . IF = 3.217 [ASEP] [ doi ]
Šilhavý, Jan - Mlejnek, Petr - Šimáková, Miroslava - Vaněčková, Ivana - Behuliak, Michal - Kuda, Ondřej - Sticová, E. - Jirsa, M. - Pravenec, Michal . Acute toxic effects of telmisartan in spontaneously hypertensive rats fed a high fructose diet . Physiological Research 2018, 67(6), 851-856 . IF = 1.701 [ASEP]

People

Ing. Michal Pravenec, DrSc.

head of the department

Ing. Jan Šilhavý, PhD.
deputy head of the department

Ing. Václav Zídek, CSc.

senior researcher

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