CETP and HDL Function in Cardiovascular Diseases

CETP和HDL在心血管疾病中的作用

基本信息

批准号：
9086414
负责人：
YUQING Eugene CHEN
金额：
$ 62万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086414
关键词：
Address Adverse effects Affect Animal Model Animals Antiatherogenic Apolipoprotein A-I Arterial Fatty Streak Atherosclerosis Belief Biological Markers Biology Blood Pressure Blood Vessels CETP gene Cardiovascular Diseases Cardiovascular Models Cholesterol Cholesterol Esters Clinical Trials Data Development Diet Drug Targeting Enzymes Event Failure Genetic Glycoproteins HDL cholesteryl ester Health High Density Lipoprotein Cholesterol High Density Lipoproteins Human Knock-out Lipoproteins Low-Density Lipoproteins Mediating Mediator of activation protein Metabolism Modeling Molecular Monitor Mus Oryctolagus cuniculus Peroxidases Pharmaceutical Preparations Pharmacologic Substance Plasma Plasma Proteins Population Protein Deficiency Protein Inhibition Proteins Research Personnel Residual state Risk Risk Factors Role Serum amyloid A protein System Technology Testing Transgenic Mice Transgenic Organisms Triglycerides Very low density lipoprotein Work atherogenesis base cardiovascular disorder risk drug development hepatic lipase improved inhibitor/antagonist knock-down mouse model novel novel marker novel strategies oxidation research and development research study torcetrapib zinc finger nuclease

项目摘要

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.

描述（由申请人提供）：胆固醇酯转移蛋白（CETP）是一种血浆糖蛋白，可介导VLDL/LDL中的甘油三酸酯的HDL胆固醇酯（CE）的交换。由于发现CETP缺乏症的人群中较高的HDL水平，CETP一直是增加HDL的有吸引力的药物靶标。这些发现促使了CETP抑制剂药物的发展。辉瑞（Pfizer）的Torcetrapib和Roche的Dalcetrapib的令人失望的发现迫切需要良好的动物模型来了解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转基因小鼠中都观察到了促乳房源性和抗动脉粥样硬化作用。与小鼠相反，兔子自然表达了CETP，并且具有与人类的脂蛋白代谢相似，因此是检查CETP抑制的更合适的模型。有趣的是，我们的初步数据成功地开发了用于心血管研究和药物开发的新型CETP基因敲除兔模型。本应用中提出的研究将对使用新型CETP基因敲除兔模型在心血管疾病中CETP和HDL功能的介体影响提供明确的表征。具体来说，我们将1）。确定CETP是否是减少兔子动脉粥样硬化的有效靶标；和2）。使用新型的转基因兔模型来定义CETP在动脉粥样硬化中的HDL功能的作用。我们的研究将对心血管疾病中对CETP和HDL生物学的理解具有深远的影响，为使用新的CETP抑制剂（即Anacetrapib和Evacetrapib）的持续临床试验提供指导，并建立相关的动物模型来评估CETP抑制剂的非靶向效应。