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Investigations in molecular and cellular model systems, in transgenic animal atherosclerosis models and in humans

Objective

Objectives

- Investigations on the patho-physiological importance of enzymatic and nonenzymatic oxidation of LDL in atherogenesis
- To study the mechanism of oxidative modification of LDL in molecular and cellular systems, in transgenic animal atherosclerosis models and in humans.
- To investigate the regulatory effects of oxidised LDL on gene expression in various cellular systems as well as its impact on foam cell formation.

Brief description:
Oxidation of LDL converts the lipoprotein to an atherogenic form which is rapidly taken up by macrophages to form lipid laden foam cells. The aim of this Concerted Action is to throw light on the in vivo mechanisms of LDL oxidation and to clarify the impact of oxidised LDL on cell physiology. Because of complexity of LDL oxidation in vivo it is intended to study this process in molecular and cellular model systems, in transgenic animal atherosclerosis models and in humans. On the molecular level LDL oxidation will be studied in enzymatic and non-enzymatic model systems with respect to structural and functional alterations of the LDL particle. Computer assisted modelling of LDL oxidation kinetics may lead to a more comprehensive understanding of the pro- and anti-oxidative processes involved. On the cellular level the mechanism of cell mediated LDL oxidation and the metabolic effects of oxidised LDL will be investigated in macrophages, endothelial cells and smooth muscle cells. Moreover, the impact of lipid metabolising enzymes on lipid deposition during in vitro foam cell formation will be studied. On the level of whole animals research will be focused on the assessment of early atherogenesis in transgenic mice atherosclerosis models. Cross breeding of established transgenic animal atherosclerosis models (apo E-knock out mice, LDL-receptor deficient mice) with mice overexpressing proteins (heat shock protein 70), cytokines (interleukin 4) or lipid oxidising enzymes (15-lipoxygenase) will be carried. In patients with familiar hypercholesterolemia the expression of pro- and anti-oxidative enzymes as well as heat shock proteins will be assessed.
Keywords:
Atherosclerosis, LDL oxidation, lipid peroxidation, oxysterols, lipoxygenase, heat shock proteins, LDL structure, foam cells, cytokines, antioxidants, PAF acetyl hydrolase, cholesterolester hydrolase

Coordinator

Humboldt-Universität zu Berlin
Address
Hessische Straße 3-4
10115 Berlin
Germany