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
人早发冠状动脉粥样硬化的发病率
人群与血浆高浓度
密度脂蛋白(HDL)及其主要载脂蛋白载脂蛋白A-I(apo
A-I)。转基因和基因敲除小鼠研究表明,循环HDL载脂蛋白
A-I主要在高水平的免疫反应中发挥“保护功能”。
致动脉粥样硬化脂蛋白通过其接受、组织和运输的能力
胆固醇从动脉到肝脏的吸收和排泄到胆汁中。
这种“胆固醇逆向转运途径”高度依赖于载脂蛋白A-I,
血浆中的酯转化。载脂蛋白A-I的能力的阻断或降低
执行此功能可导致胆固醇逆向转运减少,
外周组织胆固醇去除效率低。申请人的数据
实验表明血浆载脂蛋白构象结构改变
A-I对HDL apo A-I的形成和成熟有更深远的影响
而不仅仅是缺乏天然载脂蛋白A-I。他们的研究表明LCAT
激活,因此,血浆胆固醇酯化被抑制,
血浆中存在apo A-I的突变形式。突变型载脂蛋白A-I通过以下方式实现这一点:
抑制血浆胆固醇酯化,即使在含有天然
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中断的细胞基础,
突变型人载脂蛋白A-I的肝表达,称为6载脂蛋白A-I。该突变体
载脂蛋白A-I缺乏重复序列6,一个单一的脯氨酸间断的22聚体,
显示与已知人载脂蛋白A-I具有相似的血浆脂蛋白表型
突变,称为载脂蛋白A-I。在一个新创建的转基因小鼠模型中,
Tg 6 apo A-I申请人建议进行饮食-胆固醇喂养
研究确定突变型载脂蛋白A-I是否能预防小鼠动脉粥样硬化
高胆固醇血症他们还计划阐明分子和
6 apo A-I破坏HDL apo 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:
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资助金额:$19.5万
-
财政年份:2023
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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:
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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
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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:
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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
-
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
-
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
-
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
-
批准号:6527296
-
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
-
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
-
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
-
批准号:6390605
-
项目类别:
-
资助金额:$32.5万
-
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:
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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