The Role of Plasma Phospholipid Transfer Protein in Atherosclerosis

描述（由申请人提供）：血浆磷脂转移蛋白（PLTP）是脂质转移/脂多糖结合蛋白基因家族的成员。PLTP参与高密度脂蛋白（HDL）和含载脂蛋白B（apoB）的脂蛋白的代谢。PLTP是冠心病的独立危险因素。在小鼠模型中，已经证明PLTP缺乏减少动脉粥样硬化，而其过表达显示出相反的效果。因此，PLTP被认为是动脉粥样硬化药物干预的一个有前途的靶点。然而，这种可能性受到该物质的致动脉粥样硬化机制尚未完全理解的事实的阻碍。PLTP是一种在多种组织中表达的具有多种功能的蛋白质。为了解开复杂的机制，我们将使用在我和其他实验室产生的转基因和基因敲除小鼠模型，以测试我们的一般假设，即PLTP具有促动脉粥样硬化特性。具体目标是：1）评估PLTP过表达和PLTP缺乏代表HDL代谢和功能的两种不同状态的假设; 2）研究组织特异性PLTP过表达对脂蛋白代谢和动脉粥样硬化的影响;和3）确定组织特异性PLTP缺乏对脂蛋白代谢和动脉粥样硬化的影响。本项目将为PLTP活性与脂蛋白代谢、PLTP活性与动脉粥样硬化之间的关系提供新的信息，并将为进一步评价PLTP作为治疗靶点提供生化基础。

DESCRIPTION (provided by applicant): Plasma phospholipids transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide binding protein gene family. PLTP is involved in the metabolism of high density lipoprotein (HDL) and apolipoprotein B (apoB)-containing lipoproteins. PLTP is an independent risk factor for coronary artery disease. In mouse models, it has been demonstrated that PLTP deficiency reduces atherosclerosis while its overexpression shows the opposite effect. Therefore, PLTP is considered a promising target for pharmacological interventions on atherosclerosis. However, this possibility is hampered by the fact that the substance's atherogenic mechanism is not completely understood. PLTP is a protein with multiple functions and expressed in various tissues. In order to unravel the complex mechanisms involved, we will use the transgenic and knockout mouse models generated in my and other laboratories, to test our general hypothesis that PLTP has proatherogenic properties. The Specific Aims are: 1) to evaluate the hypothesis that PLTP overexpression and PLTP deficiency represent two distinct states in HDL metabolism and function; 2) to investigate the effect of tissue-specific PLTP overexpression on lipoprotein metabolism and atherosclerosis; and 3) to determine the effect of tissue-specific PLTP deficiency on lipoprotein metabolism and atherosclerosis. This project will provide new information on the relationship between PLTP activity and lipoprotein metabolism, between PLTP activity and atherosclerosis, and will provide biochemical basis for further evaluation of PLTP as a therapeutic target.