Molecular mechanism of novel hypolipidemics

The molecular mechanisms of novel cholesterol biosynthesis inhibitors will be studied on molecular level. For a difference with statins, which inhibitHMG CoA reductase in the early part of sterol biosynthesis path, novel derivatives inhibit enzymes in the later part and thereby do not influence the biosynthesis of some important intermediates of previous phases. The novel compounds will be tested ex vivo on a set of immortal cell lines of human hepatocytes with suppressed expression of individual gene in biosynthesis. The selected genes will be suppressed with siRNA method. Besides, compounds will be tested in in vivo conditions on hypercholesterolemic mice and genetically transformed yeast, which instead of yeast sterols synthesize human cholesterol. The acquired samples will be appointed the global profile of gene expression by using DNA microarrays and sterol profiling with HPLC and radio-detector. On the basis of analysis of performed measurements, a hypothesis of molecular action of novel compounds on molecular level will be formulated. The hypothesis will be verified by measurements of new compound inhibitory coefficient on a selected target enzyme. On the basis of confirmed hypothesis on compound action, further optimization of inhibitory compound properties will be possible by molecular modelling of enzyme - compound interactions.

Novel molecular targets and discovery of novel inhibitors of cholesterol biosynthesis are importan result for pharmaceutical science and important foo the unmet medical needs. Results of genomic analyses gave more deep insight into profile of activity of novel inhibitors as well into biological signaling pathways.

Introduction of new research areas, new scientific discoveries and technological advancement, networking of industrial and academic reserch groups, novel reserchers finishing PhD degree