CETP and HDL Function in Cardiovascular Diseases

性状（由申请方提供）：胆固醇酯转移蛋白（CETP）是一种血浆糖蛋白，介导VLDL/LDL中HDL胆固醇酯（CE）交换为甘油三酯。自从发现CETP缺乏的人群中HDL水平更高以来，CETP一直是增加HDL的有吸引力的药物靶标。这些发现促进了CETP抑制剂药物的开发。辉瑞公司的torcetrapib和罗氏公司的dalcetrapib的令人失望的发现迫切需要良好的动物模型来理解CETP抑制的分子机制和HDL的功能。小鼠缺乏CETP，并且根据小鼠背景，在人CETP转基因小鼠中观察到促动脉粥样硬化和抗动脉粥样硬化作用。与小鼠相反，兔天然表达CETP，并且具有与人类相似的脂蛋白代谢，因此是检查CETP抑制的更合适的模型。有趣的是，我们的初步数据已经成功地开发了新的CETP敲除兔模型，用于心血管研究和药物开发。本申请中提出的研究将使用新型CETP敲除兔模型提供CETP和HDL功能在心血管疾病中的介体影响的明确表征。具体来说，我们将（1）。确定CETP是否是减少兔动脉粥样硬化的有效靶点;和2）。使用新型转基因兔模型确定CETP对HDL功能性在动脉粥样硬化形成中的作用。我们的研究将对心血管疾病中CETP和HDL生物学的理解产生深远的影响，为正在进行的使用新CETP抑制剂的临床试验（即，anacetrapib和evacetrapib），并建立相关动物模型以评估CETP抑制剂的脱靶效应。

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.