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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL117491-01A1
Application #
8602046
Study Section
Special Emphasis Panel (ZRG1-VH-D (03))
Program Officer
Liu, Lijuan
Project Start
2013-08-01
Project End
2017-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$590,250
Indirect Cost
$210,668
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Fan, Jianglin; Kitajima, Shuji; Watanabe, Teruo et al. (2015) Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther 146:104-19
Yang, Dongshan; Xu, Jie; Zhu, Tianqing et al. (2014) Effective gene targeting in rabbits using RNA-guided Cas9 nucleases. J Mol Cell Biol 6:97-9
Holmen, Oddgeir L; Zhang, He; Fan, Yanbo et al. (2014) Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 46:345-51