Atherosclerosis is a chronic disease characterized by the accumulation of lipids in the arteries accompanied by a local inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) appears to affect the development o f atherosclerotic lesions through its metabolic and anti-inflammatory effects. The role of PPARa in the control of lipid and lipoprotein metabolism has been extensively studied. Moreover, the role of murine PPARa has been studied in vivo using different mo use models of atherosclerosis. However, little is known on the activity of human PPARa in vivo in the vascular system. Therefore, the Goal of this project is to characterize the role of human PPARa protein in the control of vascular inflammation using an original humanized PPARa animal model (KIPPARa mice).
To analyze the role of human PPARa protein in the atherogenic process in vivo, we will cross the KI-PPARa mice with an atherosclerotic mice model, such as the KIapoE2 mice. These mice exhibit plasma lipo protein characteristics that are equivalent to those of type III and IIB hyperlipidemic subjects, they develop spontaneous atherosclerotic lesions and they also respond to atherogenic high fat and cholesterol diets. KIPPARa mice have been recently generated in the host laboratory.
This model has been validated by checking human PPARa mRNA and protein expression in different tissues. The metabolic consequences of human PPARa expression in KIPPARa mice are currently being analysed in the host laboratory. Therefore, taking into account both models, the generation of KIPPARa; KIapoE2 mouse model will be our original main tool to carry out this project. The results are anticipated to open new perspectives for human PPARa as a molecular target for the treatment of atherosclerosis.
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