Modulators of HDL structure-function

描述（由申请人提供）：许多人群和动物研究已经确定了高密度脂蛋白（HDL）的动脉粥样硬化保护特性。除了从外周细胞提取胆固醇并将其转移到肝脏排泄（胆固醇逆向转运，RCT）的主要抗动脉粥样硬化特性外，HDL还具有抗炎和抗氧化特性。HDL治疗领域的一个新兴领域是载脂蛋白模拟肽的开发。我们已经表明，口服给药的apoA-I模拟肽导致动脉粥样硬化敏感小鼠模型中动脉粥样硬化病变形成的显著减少，尽管胆固醇水平没有变化。这通过形成具有增加的帕氧磷酶-1（PON 1）活性的preD-HDL样颗粒而发生，所述颗粒能够破坏脂质氢过氧化物（LOOH）并增强胆固醇逆向转运，这是apoA-1的主要抗动脉粥样硬化性质。因此，抗动脉粥样硬化肽调节HDL的性质，使得促动脉粥样硬化HDL转化为抗动脉粥样硬化HDL。我们提出了在抗动脉粥样硬化肽的存在下形成抗动脉粥样硬化D和preDHDL的两种机制：1）增强与ABCA 1的相互作用以形成增加水平的仅含apo A-1的颗粒，同时增加量的PON 1水平的preD-HDL颗粒;和2）增强D-HDL颗粒的受体（SRB-1）相互作用以清除胆固醇酯，从而再生活性preD-HDL颗粒。我们推测，抗动脉粥样硬化性质是由肽（肽-脂质复合物）募集HDL中存在的apoA-1、LOOH和酶如PON 1的能力决定的。例如，如果PON 1在这些颗粒上没有活性，则该HDL是炎症性的，因为它具有LOOH。为了验证我们的假设，我们提出了以下具体目标：1a肽结构对HDL组成的影响。1b肽缔合的结构方面; 2a.每种肽的抗动脉粥样硬化潜力。2b在动脉粥样硬化敏感小鼠模型中测试所选肽的抗动脉粥样硬化性质。我们将使用物理化学，体外细胞培养和动脉粥样硬化动物模型的体内研究，以表征与抗动脉粥样硬化特性相关的肽介导的HDL变化的结构和功能。这些研究将首次使我们能够了解肽调节的抗动脉粥样硬化HDL的详细结构方面以及apoA-I模拟肽的抗动脉粥样硬化和抗炎作用的机制。此外，这些研究将导致设计具有增加的抗动脉粥样硬化和抗炎效力的简单分子，并可能导致改善动脉粥样硬化的新模式。

DESCRIPTION (provided by applicant): Numerous population and animal studies have established the atheroprotective properties of high density lipoproteins (HDL). In addition to its main antiatherogenic property of extracting cholesterol from peripheral cells and transferring it to the liver for excretion (reverse cholesterol transport, RCT), HDL also possesses anti-inflammatory and antioxidant properties. An emerging area in the field of HDL therapy is the development of apolipoprotein mimetic peptides. We have shown that orally administered apoA-l-mimetic peptides result in a dramatic reduction in the atherosclerotic lesion formation in atherosclerosis-sensitive mouse models despite no change in cholesterol levels. This occurs via the formation of preD-HDL-like particles that possess increased paroxonase-1 (PON1) activity which are able to destroy lipid hydroperoxides (LOOH) and enhance reverse cholesterol transport, the major antiatherogenic properties of apoA-l. Thus antiatherogenic peptides modulate the properties of HDL such that proatherogenic HDL is converted into antiatherogenic HDL. We propose two mechanisms for the formation of both antiatherogenic D and preDHDL in the presence of antiatherogenic peptides:1) enhanced interaction with ABCA1 to form increased levels of apo A-l only containing particle with increased amounts of PON1 levels of preD-HDL particles; and 2) enhanced receptor (SRB-1) interaction of D-HDL particles to clear cholesteryl ester, thus regenerating active preD-HDL particles. We hypothesize that the antiatherogenic properties are governed by the ability of the peptide (peptide-lipid complexes) to recruit apoA-l, LOOH, and enzymes such as PON1 present in HDL. If for example, PON1 is not active on these particles, this HDL is inflammatory since it possesses LOOH. To test our hypothesis we propose the following specific aims: 1a Influence of peptide structure on:the composition of HDL. 1b Structural aspects of peptide association; 2a. Antiatherogenic potential of each peptide. 2b Testing of selected peptides for their antiatherogenic properties in atherosclerosis sensitive mouse models. We will use physical chemical, in vitro cell culture and in vivo studies in animal models of atherosclerosis to characterize the structure and function of peptide-mediated HDL changes that are related to antiatherogenic properties. These studies will for the first time enable us to understand the detailed structural aspects of peptide-modulated antiatherogenic HDL and the mechanism of antiatherogenic and anti-inflammatory actions of apoA-l-mimetic peptides. Furthermore, these studies will lead to the design of simple molecules with increased antiatherogenic and anti-inflammatory potencies and potentially lead to novel modalities to ameliorate atherosclerosis.