Modulators of HDL Structure-Function
HDL 结构-功能调节剂
基本信息
- 批准号:7466153
- 负责人:
- 金额:$ 43.36万
- 依托单位:
- 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:2008-05-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAntiatherogenicAntioxidantsApolipoproteinsApolipoproteins AAreaArterial Fatty StreakArylesteraseAtherosclerosisBiologicalBlood CirculationCell Adhesion MoleculesCellsChemicalsCholesterolCholesterol EstersClassComplexCultured CellsDevelopmentDisease regressionEndothelial CellsEnzymesExcisionExcretory functionFaceHigh Density Lipoprotein therapyHigh Density LipoproteinsHumanHydrolaseIn VitroInflammatoryInfusion proceduresLeadLesionLipid PeroxidesLipidsLipoproteinsLiverLow-Density LipoproteinsMagicMediatingMembraneMethodsModalityMolecularMolecular WeightNatural regenerationPeptidesPeripheralPhosphatidylcholine-Sterol O-AcyltransferasePlasmaPlatelet Activating FactorPopulationPositioning AttributeProductionPropertyRecruitment ActivityResolutionSamplingSolutionsStructureTestingTimeUmbilical veinanimal population studyatheroprotectivebasecytokinedesignhigh density lipoprotein-3in vivomacrophagemembrane modelmimeticsmonocytemouse modelnoveloxidized lipidparticlepeptide analogpeptide structurereceptorreconstitutionresearch studyreverse cholesterol transport
项目摘要
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. We hypothesize that this occurs via the formation of
prep-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
a and preJBHDL 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 pre(3-HDL
particles; and 2) enhanced receptor (SRB-1) interaction of a-HDL particles to clear cholesteryl ester, thus
regenerating active pre(3-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, physico-chemical, in vitro cell culture and in
vivo studies in animal models of atherosclerosis to characterize the structure and function of peptidemediated
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.
许多人口和动物研究已经建立了高密度的动脉粥样硬化保护性能,
脂蛋白(HDL)。除了从外周血中提取胆固醇的主要抗动脉粥样硬化特性外,
细胞并将其转移到肝脏进行排泄(胆固醇逆向转运,RCT),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-l-模拟物
肽导致动脉粥样硬化敏感性
尽管胆固醇水平没有变化,但小鼠模型。我们假设这是通过形成
具有增加的帕氧磷酶-1(PON 1)活性的能够破坏脂质的prep-HDL样颗粒
氢过氧化物(LOOH)和增强胆固醇逆向转运,主要抗动脉粥样硬化特性,
载脂蛋白A-1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被抑制。
转化为抗动脉粥样硬化的HDL。我们提出了两种抗动脉粥样硬化的形成机制,
a和preJBHDL在抗动脉粥样硬化肽存在下的相互作用:1)增强与ABCA 1的相互作用,以形成
仅含有载脂蛋白A-1的颗粒的水平增加,前β-HDL的PON 1水平的量增加
2)增强α-HDL颗粒的受体(SRB-1)相互作用以清除胆固醇酯,因此
再生活性前β-HDL颗粒。我们假设抗动脉粥样硬化的特性是由
肽(肽-脂质复合物)募集apoA-1、LOOH和酶如PON 1的能力
存在于HDL中。例如,如果PON 1在这些颗粒上没有活性,则这种HDL是炎症性的,因为它
拥有LOOH。为了检验我们的假设,我们提出了以下具体目标:1a。肽的影响
HDL的组成结构。1b.肽缔合的结构方面; 2a.抗动脉粥样硬化
每种肽的潜力。2b.测试所选肽的抗动脉粥样硬化性质,
动脉粥样硬化敏感小鼠模型。我们将使用物理的,物理化学的,体外细胞培养,
在动脉粥样硬化动物模型中的体内研究,以表征肽介导的
与抗动脉粥样硬化特性相关的HDL变化。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,
apoA-I-模拟肽的抗动脉粥样硬化和抗炎作用的机制。而且这些
研究将导致设计简单的分子,
并可能导致改善动脉粥样硬化的新模式。
项目成果
期刊论文数量(0)
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{{ truncateString('G M ANANTHARAMAIAH', 18)}}的其他基金
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
- 批准号:
7867924 - 财政年份:2008
- 资助金额:
$ 43.36万 - 项目类别:
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
- 批准号:
7666804 - 财政年份:2008
- 资助金额:
$ 43.36万 - 项目类别:
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
- 批准号:
8111688 - 财政年份:2008
- 资助金额:
$ 43.36万 - 项目类别:
Enhanced Hepatic Lipoprotein Uptake and Atherogenesis
增强肝脏脂蛋白摄取和动脉粥样硬化形成
- 批准号:
6527643 - 财政年份:2001
- 资助金额:
$ 43.36万 - 项目类别:
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