REGULATION OF CETP BY LIPID TRANSFER INHIBITOR PROTEIN
脂质转移抑制剂蛋白对 CETP 的调节
基本信息
- 批准号:6498972
- 负责人:
- 金额:$ 25.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-02-25 至 2004-01-31
- 项目状态:已结题
- 来源:
- 关键词:apoptosis blood lipoprotein biosynthesis blood lipoprotein metabolism cholesterol esters gene deletion mutation high density lipoproteins homeostasis human tissue immunoregulation inhibitor /antagonist laboratory rabbit lipid biosynthesis lipid metabolism lipid transport low density lipoprotein protein binding protein degradation protein structure function recombinant proteins tissue /cell culture transport proteins very low density lipoprotein
项目摘要
In human plasma, the composition and concentration of circulating lipoproteins is strongly influenced by cholesteryl ester transfer protein (CETP). Given its importance in lipoprotein metabolism and potential influence on atherosclerosis, the regulation of CETP activity has been the subject of extensive study. We have identified a plasma protein, lipid transfer inhibitor protein (LTIP), that regulates CETP activity. Recently, we purified, cloned and expressed LTIP and demonstrated its identity with apolipoprotein F, a protein with no known function. We propose that LTIP is a lipid flux switch that regulates CETP, not by suppressing CETP activity generally, but by selectively interfering with lipid transfer events to and from LDL. This selectivity toward LDL appears to be mediated by the preferential association of LTIP with LDL in plasma. Several lines of evidence from in vitro and in vivo studies strongly suggest that LTIP is a physiological modulator of lipoprotein concentration and composition. Our long-term objective is to define the role of LTIP in regulating lipoprotein metabolism and to define its impact on atherogenesis. In this proposal we further define the role of LTIP in vivo, identify its mechanism of action, and characterize mechanisms regulating its synthesis and secretion. In vitro and in vivo studies test the hypothesis that remnants of VLDL catabolism acquire LTIP as they near LDL in size, which alters their CETP-substrate status and determines the nature of the end- products of VLDL catabolism (Aim 1). Kinetic and lipid monolayer studies with recombinant LTIP, and lipoprotein modification and LTIP mutagenesis studies will determine the mechanism of LTIP's action and define the properties of lipoproteins and the structural features of LTIP that are required for activity (Aim 2). Finally, biochemical and molecular studies with cultured cells and tissue-specific expression analyses will be used to test the hypothesis that LTIP and CETP are co-expressed and co- regulated in response to cellular cholesterol homeostasis (Aim 3). Overall, these studies will provide novel insights into a poorly characterized modulator of cholesterol flux in human plasma.
在人血浆中,循环脂蛋白的组成和浓度受到胆固醇酯转移蛋白(CETP)的强烈影响。鉴于CETP在脂蛋白代谢中的重要性和对动脉粥样硬化的潜在影响,其活性的调节一直是广泛研究的主题。我们已经确定了一种血浆蛋白,脂质转移抑制蛋白(LTIP),可以调节CETP的活性。最近,我们纯化、克隆和表达了LTIP,并证明了它与载脂蛋白F(一种未知功能的蛋白质)的同源性。我们认为LTIP是调节CETP的脂质通量开关,不是通过一般抑制CETP活性,而是通过选择性地干扰LDL的脂质转移事件。这种对LDL的选择性似乎是由血浆中LTIP与LDL的优先关联介导的。来自体外和体内研究的几条证据强烈表明,LTIP是脂蛋白浓度和组成的生理调节剂。我们的长期目标是确定LTIP在调节脂蛋白代谢中的作用,并确定其对动脉粥样硬化的影响。在本文中,我们进一步明确了LTIP在体内的作用,确定了其作用机制,并描述了调节其合成和分泌的机制。体外和体内研究验证了这样的假设,即VLDL分解代谢的残留物在大小接近LDL时获得LTIP,这改变了它们的cetp底物状态,并决定了VLDL分解代谢的最终产物的性质(目的1)。重组LTIP的动力学和脂质单层研究,以及脂蛋白修饰和LTIP诱变研究将确定LTIP的作用机制,并确定脂蛋白的性质和LTIP活性所需的结构特征(目标2)。最后,将使用培养细胞和组织特异性表达分析进行生化和分子研究,以验证LTIP和CETP在响应细胞胆固醇稳态时共同表达和共同调节的假设(目的3)。总的来说,这些研究将为人类血浆中胆固醇通量的一种特性不佳的调节剂提供新的见解。
项目成果
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RICHARD E MORTON其他文献
RICHARD E MORTON的其他文献
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{{ truncateString('RICHARD E MORTON', 18)}}的其他基金
Role of cholesteryl ester transfer protein in cellular lipid homeostasis
胆固醇酯转移蛋白在细胞脂质稳态中的作用
- 批准号:
8386903 - 财政年份:2000
- 资助金额:
$ 25.81万 - 项目类别:
Role of cholesteryl ester transfer protein in cellular lipid homeostasis
胆固醇酯转移蛋白在细胞脂质稳态中的作用
- 批准号:
8038750 - 财政年份:2000
- 资助金额:
$ 25.81万 - 项目类别:
REGULATION OF CETP BY LIPID TRANSFER INHIBITOR PROTEIN
脂质转移抑制剂蛋白对 CETP 的调节
- 批准号:
6040833 - 财政年份:2000
- 资助金额:
$ 25.81万 - 项目类别:
REGULATION OF CETP BY LIPID TRANSFER INHIBITOR PROTEIN
脂质转移抑制剂蛋白对 CETP 的调节
- 批准号:
6629006 - 财政年份:2000
- 资助金额:
$ 25.81万 - 项目类别:
Regulation of CETP by lipid transfer inhibitor protein
脂质转移抑制蛋白对 CETP 的调节
- 批准号:
7233204 - 财政年份:2000
- 资助金额:
$ 25.81万 - 项目类别:
Regulation of CETP by lipid transfer inhibitor protein
脂质转移抑制蛋白对 CETP 的调节
- 批准号:
7056766 - 财政年份:2000
- 资助金额:
$ 25.81万 - 项目类别: