HUMAN LIPOPROTEIN PATHOPHYSIOLOGY
人类脂蛋白病理生理学
基本信息
- 批准号:7367221
- 负责人:
- 金额:$ 191.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-12-01 至 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant):
The overall objective of this program is to elucidate the molecular and genetic basis for abnormalities in lipoprotein metabolism that predispose to premature artery disease. The identification and characterization of such pathophysiological changes in humans will permit more rational management and better design of appropriate therapy in order to delay the onset of premature coronary artery disease. We will address this goal with four studies relating to abnormalities of high density lipoprotein (HDL). One project will focus on mapping of atherogenic traits, including LDL density, HDL level, and apolipoprotein B level in familial combined hyperlipidemia, the most common condition associated with premature therosclerosis. Mapping, followed by identification of previously undetected genes for these traits, will advance both the basic biology of lipid disorders and the potential to diagnose, prevent, and treat vascular disease. The other three projects will focus on proteins that are central to HDL metabolism: apolipoprotein (apo) A-L, phospholipids transfer protein (PLTP), and serum amyloid A (SAA). One part of the apo A-l project will focus on oxidative modifications that affect HDL's ability to remove cholesterol by the ABCA 1 pathway, a key early event in reverse cholesterol transport. Another part will identify the pathways for apo A-l reflect oxidative .in the artery wall and determine whether plasma levels of oxidized apo A-l reflect oxidative stress and inflammation. The PLTP project will uncover thebiochemical basis and functional differences of the different forms of PLTP and will identify the structural domains of PLTP and ABCA 1 that are critical for the interaction of PLTP with ABCA1 and for facilitation of lipid efflux from cells through this pathway. The study of serum amyloid A (SAA), which is carried on HDL, will explore the link between atherosclerosis and inflammation and SAA's role in HDL retention and atherosclerosis. By identifying genetic changes that lead to FCHL and alter HDL, studying proteins involved in reverse cholesterol transport (apo A-l and PLTP), and investigating the relationship between HDL and inflammation, this program project will take a multifaceted approach to elucidating the roles of HDL and related proteins in premature coronary artery disease.
描述(由申请人提供):
该项目的总体目标是阐明脂蛋白代谢异常的分子和遗传基础,脂蛋白代谢异常易患早发性动脉疾病。人类这种病理生理学变化的识别和表征将允许更合理的管理和更好的设计适当的治疗,以延迟早发性冠状动脉疾病的发作。我们将通过四项与高密度脂蛋白(HDL)异常相关的研究来实现这一目标。其中一个项目将集中于绘制致动脉粥样硬化特征,包括家族性混合型高脂血症中的LDL密度、HDL水平和载脂蛋白B水平,这是与过早治疗相关的最常见疾病。 映射,其次是识别以前未检测到的这些性状的基因,将推进脂质紊乱的基础生物学和诊断,预防和治疗血管疾病的潜力。其他三个项目将集中在对HDL代谢至关重要的蛋白质:载脂蛋白(apo)A-L,磷脂转移蛋白(PLTP)和血清淀粉样蛋白A(SAA)。载脂蛋白A-I项目的一部分将集中于影响HDL通过ABCA 1途径去除胆固醇的能力的氧化修饰,ABCA 1途径是胆固醇逆向转运的关键早期事件。另一部分将确定apo A-I在动脉壁中反映氧化的途径,并确定氧化的apo A-I的血浆水平是否反映氧化应激和炎症。PLTP项目将揭示不同形式PLTP的生化基础和功能差异,并将确定PLTP和ABCA 1的结构域,这些结构域对于PLTP与ABCA 1的相互作用以及通过该途径促进脂质从细胞流出至关重要。对血清淀粉样蛋白A(SAA)的研究,将探讨动脉粥样硬化与炎症之间的联系,以及SAA在HDL潴留和动脉粥样硬化中的作用。通过识别导致FCHL和改变HDL的遗传变化,研究参与胆固醇逆向转运的蛋白质(apo A-l和PLTP),并调查HDL与炎症之间的关系,该计划项目将采取多方面的方法来阐明HDL和相关蛋白质在早发性冠状动脉疾病中的作用。
项目成果
期刊论文数量(0)
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