CETP and HDL Function in Cardiovascular Diseases

描述(申请人提供)：胆固醇酯转移蛋白(CETP)是一种血浆糖蛋白，它介导极低密度脂蛋白/低密度脂蛋白中高密度脂蛋白胆固醇酯(CE)与甘油三酯的交换。自从在CETP缺乏的人群中发现了更高的高密度脂蛋白水平以来，CETP一直是一个有吸引力的升高高密度脂蛋白的药物靶点。这些发现促进了CETP抑制剂药物的开发。辉瑞的torcetRapib和罗氏的dalcetRapib的研究结果令人失望，迫切需要良好的动物模型来理解CETP抑制的分子机制和高密度脂蛋白的功能。小鼠缺乏CETP，在人CETP转基因小鼠中观察到了促动脉粥样硬化和抗动脉粥样硬化作用，这取决于小鼠的背景。与小鼠相比，兔自然表达CETP，并且具有与人类相似的脂蛋白代谢，因此是检测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出用于心血管研究和药物开发的新型CETP基因敲除兔模型。本申请中提出的研究将使用新的CETP基因敲除兔模型提供CETP和高密度脂蛋白功能在心血管疾病中的中介影响的明确表征。具体地说，我们将1)。确定CETP是否是减轻兔动脉粥样硬化的有效靶点；使用新的转基因兔模型确定CETP在高密度脂蛋白功能中的作用。我们的研究将对理解CETP和高密度脂蛋白在心血管疾病中的生物学作用具有深远的意义，为正在进行的使用新的CETP抑制剂(即anaceRapib和evacRapib)的临床试验提供指导，并建立相关的动物模型来评估CETP抑制剂的非靶点效应。

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.