. . "http://www.isvav.cz/projectDetail.do?rowId=GAP303/12/0472"^^ . "10"^^ . "2012-01-01+01:00"^^ . "Studium mechanizm\u016F regulace biotransforma\u010Dn\u00EDho enzymu CYP3A4 prost\u0159ednictv\u00EDm posttransla\u010Dn\u00EDch modifikac\u00ED nukle\u00E1rn\u00EDch receptor\u016F-v\u00FDznam pro terapii" . . "1"^^ . "Novel mechanisms of CYP3A4 enzyme regulation based on posttranslational modification of nuclear receptors - implications for pharmacotherapy"@en . "10"^^ . . . "1"^^ . . . "2015-04-23+02:00"^^ . . "CYP3A4 nuclear receptors gene regulation posttranslation modification"@en . . . "0"^^ . . "GAP303/12/0472" . . "CYP3A4 enzyme is the most important enzyme of drug/xenobiotic biotransformation, which metabolizes almost 50% of commonly used drugs. Nuclear receptors (NRs) such as Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are the most important ligand/xenobiotic-activated nuclear receptors responsible for both basal and inducible CYP3A4 expression. However, only little is known about functional consequences of posttranslational modifications of the NRs in hepatic CYP3A4 regulation. The aim of the project is to comprehensively describe the NRs phosphorylation patterns, examine the effects of selected kinase signaling pathways (such as Ras/Raf/ERK and AMPK) and proteasome-ubiquitin pathway on posttranslational status and activity of PXR and CAR in the hepatic regulation of CYP3A4 gene expression. The project could describe novel mechanistic aspects of CYP3A4 regulation in human hepatocytes through ERK, AMPK and proteasome signaling and have important clinical implication for personalized pharmacotherapy."@en . . . "2016-12-31+01:00"^^ . . . "Enzym CYP3A4 je nejd\u016Fle\u017Eit\u011Bj\u0161\u00EDm biotransforma\u010Dn\u00EDm enzymem \u00FA\u010Dastn\u00EDc\u00EDm se metabolismu v\u00EDce ne\u017E 50% l\u00E9\u010Div. Nukle\u00E1rn\u00ED receptory Pregnanov\u00FD X (PXR) a konstitutivn\u00ED androstanov\u00FD receptor (CAR) jsou nejd\u016Fle\u017Eit\u011Bj\u0161\u00ED transkrip\u010Dn\u00ED faktory pod\u00EDlej\u00EDc\u00ED se na konstitutivn\u00ED i inducibiln\u00ED expresi enzymu CYP3A4. \u0158ada funk\u010Dn\u00EDch posttransla\u010Dn\u00EDch modifikac\u00ED t\u011Bchto receptor\u016F byla pops\u00E1na in vitro.C\u00EDlem tohoto projektu je studovat, zdali posttransla\u010Dn\u00ED modifikace (p\u0159edev\u0161\u00EDm fosforylace a ubikvitinace) t\u011Bchto receptor\u016F zprost\u0159edkovan\u00E9 sign\u00E1ln\u00EDmi kask\u00E1dami nebo vybran\u00FDmi l\u00E9\u010Divy m\u016F\u017Eou ovlivnit expresi CYP3A4 v j\u00E1trech s konsekvencemi na celkovou biotransforma\u010Dn\u00ED schopnost pacienta. Zam\u011B\u0159\u00EDme se p\u0159edev\u0161\u00EDm na l\u00E9\u010Diva, kter\u00E1 ovliv\u0148uj\u00ED n\u011Bkter\u00E9 signaliza\u010Dn\u00ED kask\u00E1dy v hepatocytech jako jsou statiny, metformin a inhibitory proteasomu.Projekt by m\u011Bl p\u0159in\u00E9st nov\u00E9 poznatky o mechanizmech regulace CYP3A4 prost\u0159ednictv\u00EDm postransla\u010Dn\u00EDch modifikac\u00ED nukle\u00E1rn\u00EDch receptor\u016F s klinick\u00FDmi implikacemi pro personalizovanou farmakoterapii." . "2014-04-18+02:00"^^ . .