APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS
APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS
批准号:
6192276
负责人:
Mary G Sorci-Thomas
金额:
$32.62万
依托单位国家:
美国
项目类别:
财政年份:
2000
资助国家:
美国
项目状态:
已结题
起止时间:
2000-09-15 至 2004-07-31
关键词:
apolipoproteins atherosclerosis conformation electron microscopy enzyme inhibitors gene mutation genetically modified animals high density lipoproteins hypercholesterolemia immunoprecipitation laboratory mouse phosphatidylcholine sterol acyltransferase protein structure structural biology transfection
中文摘要
早期冠状动脉粥样硬化在人类中的发生率
人口与血浆HIGH浓度的降低高度相关
密度脂蛋白及其主要载脂蛋白载脂蛋白A-I
A-I)。转基因和基因敲除小鼠的研究表明,循环中的高密度脂蛋白载脂蛋白
A-I主要起到保护作用,以应对高水平的
脂蛋白通过其接受、组织和运输的能力而致动脉粥样硬化
胆固醇从动脉到肝脏的摄取和排泄到胆汁中。
这种“反向胆固醇运输途径”高度依赖于载脂蛋白A-I的
酯在血浆中的转化。阻断或降低载脂蛋白A-I的能力
执行这一功能可以减少胆固醇的反向转运和
对外周组织胆固醇的清除效率低下。申请者的数据
实验室研究表明,血浆载脂蛋白构象的结构变化
A-I对高密度脂蛋白载脂蛋白A-I的形成和成熟有更深远的影响
而不仅仅是缺少本地的载脂蛋白A-I。他们的研究表明,LCAT
激活,从而抑制血浆胆固醇的酯化
血浆中存在突变形式的载脂蛋白A-I。突变的载脂蛋白A-I通过
即使在含有天然胆固醇的血浆中也能抑制血浆胆固醇的酯化
或野生型载脂蛋白A-I。因此,他们建议研究分子和
高密度脂蛋白代谢严重紊乱的细胞学基础
突变的人载脂蛋白A-I在肝脏中的表达,命名为6-载脂蛋白A-I。这个突变体
载脂蛋白A-I缺少重复6,一个由22个聚体组成的单一脯氨酸,一直是
与已知的人类载脂蛋白A-I具有相似的血浆脂蛋白表型
突变,称为载脂蛋白A-I。在一种新创建的转基因小鼠模型中,被命名为
TG6载脂蛋白A-I申请人建议进行膳食胆固醇喂养
确定突变载脂蛋白A-I是否对小鼠动脉粥样硬化有保护作用的研究
患有高胆固醇血症。他们还计划阐明分子和
6-载脂蛋白A-I干扰高密度脂蛋白A-I代谢的细胞基础
英文摘要
The incidence of premature coronary atherosclerosis in the human
population is highly correlated to decreased concentrations of plasma high
density lipoproteins (HDL) and its major apoprotein, apolipoprotein A-I (apo
A-I). Transgenic and knockout mouse studies have shown that circulating HDL apo
A-I primarily plays a "protective function" in response to high levels of
atherogenic lipoproteins through its ability to accept, organize and transport
cholesterol out of the artery to the liver for uptake and excretion into bile.
This "reverse cholesterol transport pathway" is highly dependent upon apo A-I's
ester conversion in the plasma. Blockage or reduction in apo A-I's ability to
carry out this function can lead to reduced reverse cholesterol transport and
inefficient removal of peripheral tissue cholesterol. Data from the applicants'
laboratory show that structural alterations in the conformation of plasma apo
A-I can have a more profound effect on HDL apo A-I formation and maturation
than merely the absence of native apo A-I alone. Their studies show that LCAT
activation and thus, plasma cholesterol esterification is inhibited by the
presence of a mutant form of apo A-I in plasma. The mutant apo A-I does this by
inhibiting plasma cholesterol esterification even in plasma containing native
or wild type apo A-I. Thus, they propose to investigate the molecular and
cellular basis for the severe disruption in HDL metabolism resulting from the
hepatic expression of the mutant human apo A-I, termed 6 apo A-I. This mutant
of apo A-I lacks repeat 6, a single proline punctuated 22-mer and has been
shown to have a similar plasma lipoprotein phenotype to a known human apo A-I
mutation, called apo A-I. In a newly created transgenic mouse model, designated
Tg6 apo A-I the applicants propose to conduct dietary-cholesterol feeding
studies to determine if mutant apo A-I protects against atherosclerosis in mice
with hypercholesterolemia. They also plan to elucidate the molecular and
cellular basis for 6 apo A-I's disruption of HDL apo A-I metabolism.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Role of Pcpe2 in Adipose Tissue Remodeling and Lipoprotein Metabolism
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批准号:10837655
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项目类别:
-
资助金额:$19.5万
-
财政年份:2023
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Biogenesis of HDL Through Cholesterol Efflux and ApoA-I Structural Reorganization
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批准号:8874470
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项目类别:
-
资助金额:$54.72万
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财政年份:2015
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负责人:Mary G Sorci-Thomas
-
依托单位:
Structural Relationship Between APO A-1 Comformation and the Extent of Particle L
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批准号:7537462
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项目类别:
-
资助金额:$25.74万
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财政年份:2008
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负责人:Mary G Sorci-Thomas
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依托单位:
2006 Lipoprotein Metabolism Gordon Conference
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批准号:7158527
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项目类别:
-
资助金额:$1.3万
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财政年份:2006
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负责人:Mary G Sorci-Thomas
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依托单位:
Structure/Function Relationships of APO A-I
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批准号:7000693
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项目类别:
-
资助金额:$24.86万
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财政年份:2004
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负责人:Mary G Sorci-Thomas
-
依托单位:
STRUCTURE/FUNCTION RELATIONSHIPS OF APOLIPOPROTEIN A (APOA-1)
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批准号:6338878
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项目类别:
-
资助金额:$19.92万
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财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation, Atherosclerosis and ApoA-I
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批准号:8402617
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项目类别:
-
资助金额:$34.87万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation, Atherosclerosis and ApoA-I
-
批准号:7802602
-
项目类别:
-
资助金额:$37.0万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS
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批准号:6527296
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项目类别:
-
资助金额:$32.4万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation, Atherosclerosis and ApoA-I
-
批准号:8206793
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项目类别:
-
资助金额:$36.63万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS
-
批准号:6642190
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项目类别:
-
资助金额:$32.4万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS
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批准号:6390605
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项目类别:
-
资助金额:$32.5万
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财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation and Inhibition of Cholesterol Transport
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批准号:7391723
-
项目类别:
-
资助金额:$34.02万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation, Atherosclerosis and ApoA-I
-
批准号:8009498
-
项目类别:
-
资助金额:$37.0万
-
财政年份:2000
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation and Inhibition of Cholesterol Transport
-
批准号:7065590
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项目类别:
-
资助金额:$35.03万
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财政年份:1999
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负责人:Mary G Sorci-Thomas
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依托单位:
Inflammation and Inhibition of Cholesterol Transport
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批准号:7212080
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项目类别:
-
资助金额:$34.02万
-
财政年份:1999
-
负责人:Mary G Sorci-Thomas
-
依托单位:
Inflammation and Inhibition of Cholesterol Transport
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批准号:6927680
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项目类别:
-
资助金额:$35.88万
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财政年份:1999
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负责人:Mary G Sorci-Thomas
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依托单位:
STRUCTURE/FUNCTION RELATIONSHIPS OF APOLIPOPROTEIN A (APOA-1)
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批准号:6110212
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项目类别:
-
资助金额:$19.92万
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财政年份:1999
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负责人:Mary G Sorci-Thomas
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依托单位:
STRUCTURE/FUNCTION RELATIONSHIPS OF APOLIPOPROTEIN A (APOA-1)
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批准号:6272925
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项目类别:
-
资助金额:$18.6万
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财政年份:1998
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负责人:Mary G Sorci-Thomas
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依托单位:
STRUCTURE/FUNCTION RELATIONSHIPS OF APOLIPOPROTEIN A (APOA-1)
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批准号:6242227
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项目类别:
-
资助金额:$21.03万
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财政年份:1997
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负责人:Mary G Sorci-Thomas
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依托单位:
海外基金