权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Apo E mimetics reduce cholesterol and improve HDL function

Apo E 模拟物可降低胆固醇并改善 HDL 功能

基本信息

批准号：
8111688
负责人：
G M ANANTHARAMAIAH
金额：
$ 41.3万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111688
关键词：
Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Apolipoprotein A-I Apolipoprotein E Apolipoproteins B Atherogenic Diet Atherosclerosis Binding Cardiovascular Diseases Cell surface Cells Cholesterol Cholesterol Ester Transfer Proteins Cholesterol Homeostasis Chronic Clear Cell Disease E protein Electrons Exhibits Face Health Heparan Sulfate Proteoglycan Hepatic Hepatocyte High Density Lipoproteins In Vitro Inflammatory Knockout Mice Lead Lesion Link Lipid Peroxides Lipids Lipoproteins Low-Density Lipoproteins Mediating Modeling Mus New Zealand Oryctolagus cuniculus Pathway interactions Peptides Plasma Property Proteins Reagent Recycling Research Saline Tertiary Protein Structure Therapeutic Agents Very low density lipoprotein aryldialkylphosphatase atherogenesis cardiovascular risk factor design feeding improved intravenous administration mimetics mouse model novel novel therapeutics particle receptor binding reverse cholesterol transport uptake

项目摘要

DESCRIPTION (provided by applicant): An ideal treatment for atherosclerosis would involve rapid clearance of plasma cholesterol and inhibition of inflammatory pathways. Recent advances in apoA-I mimetic peptides indicate the possibility of improving HDL functions. This proposal deals with ways of incorporating properties of lowering plasma apolipoprotein B- containing lipoproteins with properties of improving HDL function. Our hypothesis is that such peptides would not only retain properties that improve HDL functions, but also enhance the clearance of apoB-containing lipoproteins, thus lowering plasma cholesterol levels. Thus, we designed novel peptides that possesses the cationic putative receptor binding domain from apoE that is covalently linked to an active apoA-I mimetic peptide domain. We have also designed a single-domain cationic peptide to which we have incorporated the lipid hydroperoxide-scavenging properties of apoA-I mimetics. Preliminary results show that these properties enhance uptake of atherogenic lipoproteins in HepG2 cells and inhibit atherosclerosis in apoE null mice. They also appear to improve HDL function. We have exciting results to show that Ac-hE-18A-NH2 dramatically decreases plasma cholesterol in different dyslipidemic mouse models and WHHL rabbits. Preliminary results also show that the peptide possesses antiinflammatory properties. This occurs through a lowering of plasma lipid hydroperoxide levels concomitant with a significant increase in plasma paraoxonase activity. In the WHHL model, the LDL-R pathway is compromised, thus the peptide-mediated atherogenic lipoprotein clearance is likely via the cell surface heparan sulfate proteoglycan (HSPG)-mediated pathway, as described earlier by us in murine models. In a second rabbit model of atherosclerosis, New Zealand White (NZW) rabbits fed an atherogenic diet, a single intravenous administration (3mg/kg) of the peptide significantly decreased total plasma cholesterol levels for 15 days. En face analysis of the lesions after 50 days showed approximately 50% lesion coverage in the saline administered rabbits (control), while little to no lesion in the peptide-treated animals. We therefore hypothesize that both cholesterol-dependent and -independent properties of these novel peptides contribute to the beneficial effects of the peptides to inhibit atherogenesis. We propose two specific aims to further investigate the mechanism of action of these two types of peptides: Specific Aim 1: Effect of peptides on A) uptake of apoB-containing lipoproteins in hepatocytes isolated from different dyslipidemic mouse models and rabbit models and in HepG2 cells. B) Changes in apoA-I and apoE-containing particles and their anti- inflammatory properties. Specific Aim 2: Effect of peptides on A) plasma cholesterol levels, B) lesion inhibition in animal models of atherosclerosis, and C) modulation of HDL properties. Research towards the understanding of the antiatherogenic properties of these novel peptides would yield a better understanding of cholesterol homeostasis and could lead to novel therapeutic reagents that would be useful in the treatment of atherosclerosis and its sequelae. PUBLIC HEALTH RELEVANCE: An ideal treatment for atherosclerosis would involve rapid clearance of plasma cholesterol and inhibition of inflammatory pathways. Recent advances in apoA-I mimetic peptides indicate the possibility of improving HDL function. This proposal deals with ways of incorporating properties of lowering plasma apolipoprotein B- containing lipoproteins with properties of improving HDL function. This is hypothesized to preserve both the anti- inflammatory and cholesterol reducing functions in designed peptides in order to obtain a peptide that would be ideal for the treatment of atherosclerosis and related lipid related inflammatory disorders.

描述（由申请人提供）：动脉粥样硬化的理想治疗包括快速清除血浆胆固醇和抑制炎症途径。apoA-I模拟肽的最新进展表明了改善HDL功能的可能性。该建议涉及将降低血浆含载脂蛋白B的脂蛋白的性质与改善HDL功能的性质相结合的方法。我们的假设是，这样的肽将不仅保留改善HDL功能的特性，而且还增强含载脂蛋白B的脂蛋白的清除，从而降低血浆胆固醇水平。因此，我们设计了新的肽，其具有来自apoE的阳离子推定受体结合结构域，该结构域共价连接到活性apoA-I模拟肽结构域。我们还设计了一种单结构域阳离子肽，我们已将脂质过氧化氢清除apoA-I模拟物的特性。初步结果表明，这些特性增强了HepG 2细胞中致动脉粥样硬化脂蛋白的摄取，并抑制apoE基因敲除小鼠的动脉粥样硬化。它还可以改善HDL功能。我们有令人兴奋的结果表明，Ac-hE-18 A-NH 2在不同的血脂异常小鼠模型和WHHL兔中显著降低血浆胆固醇。初步结果还表明，该肽具有生物活性。这是通过降低血浆脂质氢过氧化物水平，同时显著增加血浆对氧磷酶活性而发生的。在WHHL模型中，LDL-R途径受损，因此肽介导的致动脉粥样硬化脂蛋白清除可能通过细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）介导的途径，如我们之前在鼠模型中所述。在动脉粥样硬化的第二个兔模型中，新西兰白色（NZW）兔喂食致动脉粥样硬化饮食，单次静脉内施用（3 mg/kg）肽15天显著降低总血浆胆固醇水平。50天后的损伤的正面分析显示在施用盐水的兔（对照）中约50%的损伤覆盖，而在肽处理的动物中几乎没有损伤。因此，我们假设这些新肽的胆固醇依赖性和非依赖性特性有助于肽抑制动脉粥样硬化形成的有益作用。我们提出了两个具体的目标，以进一步研究这两种类型的肽的作用机制：具体目标1：肽对A）从不同的血脂异常小鼠模型和兔模型分离的肝细胞和HepG 2细胞中摄取含apoB的脂蛋白的影响。B）含apoA-I和apoE的颗粒的变化及其抗炎性质。具体目标二：肽对A）血浆胆固醇水平，B）动脉粥样硬化动物模型中损伤抑制，和C）HDL性质调节的作用。对这些新肽的抗动脉粥样硬化性质的理解的研究将产生对胆固醇稳态的更好的理解，并可能导致新的治疗试剂，这将是有用的动脉粥样硬化及其后遗症的治疗。公共卫生相关性：动脉粥样硬化的理想治疗包括快速清除血浆胆固醇和抑制炎症途径。apoA-I模拟肽的最新进展表明了改善HDL功能的可能性。该建议涉及将降低血浆含载脂蛋白B的脂蛋白的性质与改善HDL功能的性质相结合的方法。这被假设为在设计的肽中保留抗炎和降低胆固醇的功能，以获得对于治疗动脉粥样硬化和相关的脂质相关的炎性病症是理想的肽。