Atheroregression via Enhanced Reverse Cholesterol Transport
通过增强反向胆固醇转运实现动脉粥样硬化消退
基本信息
- 批准号:8819557
- 负责人:
- 金额:$ 58.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-04-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAnti-Inflammatory AgentsAnti-inflammatoryApolipoprotein A-IApolipoprotein A-IIApolipoprotein EApoproteinsArterial Fatty StreakAtherosclerosisBacterial ProteinsBase CompositionBindingBiochemicalBlood flowCell LineCell modelCellsChemicalsCholesterolCholesterol EstersComplementary therapiesComplexData ReportingDiseaseDockingDoseEthersEtiologyExcisionFutureGoalsHepaticHepatocyteHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHumanIn VitroInjection of therapeutic agentIntestinesIntravenousLDL Cholesterol LipoproteinsLearningLipidsLipoprotein (a)LiverMediatingMethodsModalityModelingMusMyocardial InfarctionPaperPatientsPharmaceutical PreparationsPhosphatidylcholine-Sterol O-AcyltransferasePlasmaPlasma ProteinsProcessPropertyProteinsPublic HealthRadioReactionRecombinantsRecruitment ActivityRecyclingSalineSeriesSiteStagingStreptococcus pyogenesStrokeSurfaceTestingVirulence FactorsWaterarterial lesionbasebile saltscell typechemical kineticshigh riskimprovedin vivolipid disordermacrophagemorphometrymouse modelnonhuman primatenovelopacity factorreceptorreceptor bindingresponsereverse cholesterol transportsuccesssyndecanuptake
项目摘要
DESCRIPTION (provided by applicant): Cholesterol, a water insoluble compound, is a major player in the etiology of atherosclerosis. Cholesterol accumulates in plaques in the arterial wall causing obstructed blood flow leading to heart attacks and strokes. Despite the success of the statin class of cholesterol-lowering drugs, which reduce plasma LDL-cholesterol, there remains an unfulfilled need for complementary therapies that promote the removal of cholesterol from atherosclerotic lesions and its transfer to the liver for disposal. We identified a bacterial protein, serum opacity factor (SOF) that at low doses (0.004 mg) rapidly (6 min) and profoundly reduces by half the plasma cholesterol in mice. On the basis of studies with liver cells, we learned that SOF treatment promotes hepatic cholesterol uptake by multiple receptors that bind to a plasma protein, apolipoprotein E. Our plans are to move these discoveries closer to human therapy by completion of several objectives. The first is to show in primary human hepatocytes that the mechanisms for cholesterol removal are as efficient as they are in hepatic cell lines and in mouse liver cells. The second is to determine the contributions of each relevant liver receptor to cholesterol removal. This information would be useful in making choices about the most appropriate co therapy, e.g., a statin. Third, we will show that SOF increases the transfer of cholesterol from macrophages, an important cell type in all stages of atherosclerosis, to the liver for disposal. Lastly, we will show that SOF reverses atherosclerosis in mice. Completion of these objectives would pave the way to future studies in non human primates and ultimately in high risk patients with atherosclerosis. Methods: Radio trace cholesterol uptake and removal by liver cells in response to SOF; use chromatographic methods to show in cells and mice that SOF promotes conversion of macrophage-cholesterol to water-soluble bile salts that enter the intestine for disposal; characterize in mice the changes in response to SOF in the quantity and quality of arterial lesions by chemical analysis and morphometry.
描述(由申请人提供):胆固醇是一种不溶性化合物,是动脉粥样硬化病因的主要参与者。胆固醇在动脉壁的斑块中积聚,导致血液流动导致心脏病发作和中风。尽管毒药降低血浆LDL-胆固醇的汀类药物类别的成功,但仍需要对互补疗法的需求,这些疗法促进了从动脉粥样硬化病变中去除胆固醇及其转移到肝脏处置的胆固醇。我们确定了一种细菌蛋白,血清不透明度因子(SOF),该因子在低剂量(0.004 mg)中迅速(6分钟),并将小鼠中血浆胆固醇的一半降低一半。根据对肝细胞的研究,我们了解到,SOF治疗促进了与血浆蛋白结合的多种受体促进肝胆固醇的吸收。载脂蛋白E。我们的计划是通过完成几种目标来使这些发现更接近人类治疗。首先是在原代人肝细胞中表明,去除胆固醇的机制与肝细胞系和小鼠肝细胞中一样有效。第二个是确定每个相关肝受体对去除胆固醇的贡献。此信息对于选择最合适的CO治疗,例如他汀类药物将很有用。第三,我们将表明,SOF将胆固醇从巨噬细胞(在动脉粥样硬化的各个阶段)中的巨噬细胞转移到肝脏以处置。最后,我们将表明SOF逆转小鼠的动脉粥样硬化。这些目标的完成将为未来的非人类灵长类动物的研究铺平道路,并最终在高风险患者患有动脉粥样硬化的患者中铺平道路。方法:响应SOF的无线电痕量胆固醇吸收和肝细胞去除;使用色谱方法在细胞和小鼠中显示SOF促进巨噬细胞 - 胆固醇向水溶性胆汁盐的转化,这些胆汁盐进入肠道以处置;在小鼠中表征了通过化学分析和形态计量学对SOF的响应变化。
项目成果
期刊论文数量(63)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enhancing reverse cholesterol transport: the case for phosphatidylcholine therapy.
增强反向胆固醇转运:磷脂酰胆碱治疗的案例。
- DOI:10.1097/01.mol.0000169345.15450.4b
- 发表时间:2005
- 期刊:
- 影响因子:4.4
- 作者:Pownall,HenryJ;Ehnholm,Christian
- 通讯作者:Ehnholm,Christian
Role of cysteine residues in human plasma phospholipid transfer protein.
半胱氨酸残基在人血浆磷脂转移蛋白中的作用。
- DOI:10.1023/a:1020628006453
- 发表时间:1999
- 期刊:
- 影响因子:0
- 作者:Qu,SJ;Fan,HZ;Kilinc,C;Pownall,HJ
- 通讯作者:Pownall,HJ
Pro-apoptotic low-density lipoprotein subfractions in type II diabetes.
II 型糖尿病中促凋亡的低密度脂蛋白亚组分。
- DOI:10.1016/j.atherosclerosis.2006.08.059
- 发表时间:2007
- 期刊:
- 影响因子:5.3
- 作者:Yang,Chao-yuh;Chen,Hsin-Hung;Huang,MaxT;Raya,JoeL;Yang,Jun-Hai;Chen,Chu-Huang;Gaubatz,JohnW;Pownall,HenryJ;Taylor,AddisonA;Ballantyne,ChristieM;Jenniskens,FloorA;Smith,CharlesV
- 通讯作者:Smith,CharlesV
Regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) synthesis, degradation, and translocation by high-density lipoprotein(2) at a low concentration.
低浓度高密度脂蛋白 (2) 对酰基辅酶 A:胆固醇酰基转移酶 (ACAT) 合成、降解和易位的调节。
- DOI:10.1161/01.atv.20.12.2636
- 发表时间:2000
- 期刊:
- 影响因子:0
- 作者:Li,L;Pownall,HJ
- 通讯作者:Pownall,HJ
Efficient nuclear delivery of antisense oligodeoxynucleotides and selective inhibition of CETP expression by apo E peptide in a human CETP-stably transfected CHO cell line.
在人 CETP 稳定转染的 CHO 细胞系中,反义寡脱氧核苷酸的有效核递送和载脂蛋白 E 肽对 CETP 表达的选择性抑制。
- DOI:10.1161/01.atv.19.9.2207
- 发表时间:1999
- 期刊:
- 影响因子:0
- 作者:Liu,K;Ou,J;Saku,K;Jimi,S;Via,DP;Sparrow,JT;Zhang,B;Pownall,HJ;Smith,LC;Arakawa,K
- 通讯作者:Arakawa,K
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Henry J. Pownall其他文献
Mechanism and kinetics of transfer of a fluorescent fatty acid between single-walled phosphatidylcholine vesicles.
单壁磷脂酰胆碱囊泡之间荧光脂肪酸转移的机制和动力学。
- DOI:
10.1021/bi00542a017 - 发表时间:
1980 - 期刊:
- 影响因子:2.9
- 作者:
Michael C. Doody;Henry J. Pownall;Yin J. Kao;Louis C. Smith - 通讯作者:
Louis C. Smith
TRIGLYCERIDE LEVELS AND ITS RELATIONSHIP WITH HEMOGLOBIN A1C IN PATIENTS WITH DIABETES
- DOI:
10.1016/s0735-1097(16)32021-6 - 发表时间:
2016-04-05 - 期刊:
- 影响因子:
- 作者:
Reynaria Pitts;Katelyn Garcia;Paul Ribisl;Mara Vitolins;Lawrence Cheskin;Stephen Glasser;Ashok Balasubramanyam;Henry J. Pownall;Lynne Wagenknecht;Robert Eckel - 通讯作者:
Robert Eckel
HDL-free cholesterol influx into macrophages and transfer to LDL correlate with HDL-free cholesterol content
- DOI:
10.1016/j.jlr.2024.100707 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:
- 作者:
Dedipya Yelamanchili;Baiba K. Gillard;Antonio M. Gotto;Miguel Caínzos Achirica;Khurram Nasir;Alan T. Remaley;Corina Rosales;Henry J. Pownall - 通讯作者:
Henry J. Pownall
Commentary on SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect fatty acid translocation
- DOI:
10.1194/jlr.c120000745 - 发表时间:
2020-05-01 - 期刊:
- 影响因子:
- 作者:
Henry J. Pownall - 通讯作者:
Henry J. Pownall
Dietary ethanol is associated with reduced lipolysis of intestinally derived lipoproteins.
- DOI:
- 发表时间:
1994-12 - 期刊:
- 影响因子:6.5
- 作者:
Henry J. Pownall - 通讯作者:
Henry J. Pownall
Henry J. Pownall的其他文献
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{{ truncateString('Henry J. Pownall', 18)}}的其他基金
Atheroprotection via Reduced Plasma High Density Lipoprotein-Free Cholesterol Bioavailability
通过降低血浆高密度脂蛋白胆固醇生物利用度来预防动脉粥样硬化
- 批准号:
10523525 - 财政年份:2019
- 资助金额:
$ 58.63万 - 项目类别:
Atheroprotection via Reduced Plasma High Density Lipoprotein-Free Cholesterol Bioavailability
通过降低血浆高密度脂蛋白胆固醇生物利用度来预防动脉粥样硬化
- 批准号:
10063905 - 财政年份:2019
- 资助金额:
$ 58.63万 - 项目类别:
Atheroprotection via Reduced Plasma High Density Lipoprotein-Free Cholesterol Bioavailability
通过降低血浆高密度脂蛋白胆固醇生物利用度来预防动脉粥样硬化
- 批准号:
10308045 - 财政年份:2019
- 资助金额:
$ 58.63万 - 项目类别:
High Density Lipoprotein Biogenesis and Speciation
高密度脂蛋白生物发生和形态形成
- 批准号:
9164514 - 财政年份:2016
- 资助金额:
$ 58.63万 - 项目类别:
High Density Lipoprotein Biogenesis and Speciation
高密度脂蛋白生物发生和形态形成
- 批准号:
9321088 - 财政年份:2016
- 资助金额:
$ 58.63万 - 项目类别:
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