DESCRIPTION (provided by applicant): Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that mediates the exchange of HDL cholesteryl esters (CE) for triglycerides in VLDL/LDL. The CETP has been an attractive drug target for increasing HDL since the discovery of higher HDL levels in populations with CETP deficiency. These findings prompted the development of CETP inhibitor drugs. The disappointing findings of Pfizer's torcetrapib and Roche's dalcetrapib are desperately requiring good animal models to understand molecular mechanisms of CETP inhibition and the functions of HDL. Mice lack CETP and both proatherogenic and antiatherogenic effects have been observed in human CETP transgenic mice depending on the mouse background. In contrast to mice, rabbits express CETP naturally and have a similar lipoprotein metabolism to that of humans, and thus are a more appropriate model to examine CETP inhibition. Intriguingly, our preliminary data have successfully developed novel CETP knockout rabbit models for cardiovascular research and drug development. The studies proposed in this application will provide a definitive characterization of the mediator influence of CETP and HDL functions in cardiovascular diseases using novel CETP knockout rabbit models. Specifically, we will 1). Determine whether CETP is an effective target for reducing atherosclerosis in rabbits; and 2). Define the roles of CETP on HDL functionality in atherogenesis using novel transgenic rabbit models. Our studies will have profound implications on the understanding of CETP and HDL biology in cardiovascular diseases, provide guidance to ongoing clinical trials using new CETP inhibitors (i.e., anacetrapib and evacetrapib), and establish a relevant animal model to evaluate off-target effects of CETP inhibitors.

PUBLIC HEALTH RELEVANCE: The disappointing findings of Pfizer's torcetrapib in 2006 and Roche's dalcetrapib in 2012 are desperately requiring good animal models to understand molecular mechanisms of cholesteryl ester transfer protein (CETP) inhibition and the functions of HDL. Mice lack CETP and both proatherogenic and antiatherogenic effects have been observed in human CETP transgenic mice depending on the mouse background. In contrast to mice, rabbits express CETP naturally and have similar lipoprotein metabolism to that of humans, and thus are a more appropriate model to examine CETP inhibition. The studies proposed in this application will provide a definitive characterization of the mediator influence o CETP and HDL functions in CVD using novel CETP knockout rabbit models. Our studies will have profound implications on the understanding of CETP and HDL biology in cardiovascular diseases.