HUMAN LIPOPROTEIN PATHOPHYSIOLOGY

人类脂蛋白病理生理学

• 批准号: 6850936
• 负责人: JOHN J ALBERS
• 金额: $ 195.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/6850936
• 关键词: atherosclerosis; blood lipoprotein metabolism; blood lipoprotein transport; cardiovascular disorder risk; clinical research; familial hyperlipoproteinemia; lipoprotein disorder

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)： 该计划的总体目标是阐明脂蛋白代谢异常的分子和遗传基础，这些异常容易导致早产儿动脉疾病。对人类这种病理生理变化的识别和表征将允许更合理的管理和更好地设计适当的治疗方法，以延迟过早冠状动脉疾病的发生。我们将通过四项与高密度脂蛋白(HDL)异常相关的研究来解决这一目标。其中一个项目将侧重于绘制动脉粥样硬化的特征图，包括家族性混合性高脂血症的低密度脂蛋白密度、高密度脂蛋白水平和载脂蛋白B水平，这是与过早动脉粥样硬化有关的最常见情况。绘制图谱，然后识别以前未检测到的这些特征的基因，将促进血脂紊乱的基本生物学以及诊断、预防和治疗血管疾病的可能性。其他三个项目将专注于对高密度脂蛋白代谢至关重要的蛋白质：载脂蛋白A-L、磷脂转移蛋白和血清淀粉样蛋白A。载脂蛋白A-L项目的一部分将专注于影响高密度脂蛋白通过ABCA 1途径清除胆固醇的氧化修饰，ABCA 1途径是胆固醇反向运输的关键早期事件。另一部分将确定载脂蛋白A-L在动脉壁反映氧化应激的途径，并确定血浆氧化载脂蛋白A-L水平是否反映氧化应激和炎症反应。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ABCA1的结构域，这些结构域对于PLTP与ABCA1的相互作用以及通过这一途径促进细胞脂质外流至关重要。对血清淀粉样蛋白A(SAA)的研究将探索动脉粥样硬化和炎症之间的联系，以及SAA在高密度脂蛋白滞留和动脉粥样硬化中的作用。通过识别导致FCHL和改变高密度脂蛋白的基因变化，研究参与胆固醇反向运输的蛋白质(载脂蛋白A-L和PLTP)，以及研究高密度脂蛋白与炎症的关系，该项目将采取多方面的方法来阐明高密度脂蛋白和相关蛋白质在过早冠状动脉疾病中的作用。