LYSOSOMES AND ATHEROSCLEROTIC FOAM CELL GENESIS

溶酶体和动脉粥样硬化泡沫细胞起源

• 批准号: 2225259
• 负责人: WALTER G JEROME
• 金额: $ 15.24万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2225259
• 关键词: atherosclerosis; blood lipoprotein metabolism; cholesterol; esterification; high voltage electron microscopy; histochemistry /cytochemistry; hydrolysis; intracellular transport; low density lipoprotein; lysosomes; macrophage; pathologic process; pigeons; video microscopy

At specific important stages of atherosclerosis, foam cells accumulate cholesterol within large swollen lysosomes. Numerous studies have suggested the importance of this phenomenon in the pathogenesis of the disease, but the cause of this lysosomal accumulation is unknown. The long term goal of our research is to understand both the mechanism and importance of lysosomal lipid engorgement in atherogenesis. The experiments proposed in this application will explore the mechanism by which lysosomal lipid accumulation occurs. For these studies, two lipoproteins will be used to load cholesterol into cells. One (ox-LDL) promotes significant lysosomal accumulation of cholesterol (ox-LDL) while cholesterol from the other (ac-LDL) appears to be efficiently cleared from lysosomes and accumulates within cytoplasmic inclusion. We will compare metabolism of cholesterol from these two lipoproteins in order to correlate differences with alterations in their storage patterns. This involves relating quantitative ultrastructural data on lipid accumulation within lysosomes and cytoplasmic inclusions to biochemical measures of cholesterol metabolism and accumulation. Specifically, we will determine to what extent cellular transport, lysosomal hydrolysis, cytoplasmic reesterification, cytoplasmic hydrolysis, and cellular cholesterol efflux play a role in lysosomal accumulation. As an early occurrence in atherogenesis, lysosomal lipid accumulation is potentially very important in disease progression. The integrated use of ultrastructural quantitation and lipid biochemistry will provide a detailed understanding of the mechanism of this early event and, in turn, will help better define the mechanism of this early event and, in turn, will help better define the process of atherosclerotic lesion progression. In addition, the research could provide important clues as to possible early treatment modalities.

在动脉粥样硬化的特定重要阶段，泡沫细胞积累 大肿胀溶酶体内的胆固醇。 有许多研究 提出了这种现象在 疾病，但这种溶酶体积累的原因尚不清楚。 长 我们研究的一项目标是了解机制和 溶酶体脂质在动脉粥样硬化中的重要性。 这 本应用程序中提出的实验将通过 发生哪些溶酶体脂质积累。 对于这些研究，两个 脂蛋白将用于将胆固醇加载到细胞中。 一个（ox-dll） 促进胆固醇（OX-LDL）的显着溶酶体积累，而 来自另一个（AC-LDL）的胆固醇似乎可以有效地从 溶酶体并积聚在细胞质包含中。 我们将比较 从这两种脂蛋白中胆固醇的代谢，以便相关 随着其存储模式改变的差异。 这涉及 有关脂质积累的定量超微结构数据 溶酶体和细胞质内包含胆固醇生化测量 代谢和积累。 具体来说，我们将确定什么 细胞转运，溶酶体水解，细胞质 重新酯化，细胞质水解和细胞胆固醇外排 在溶酶体积累中起作用。 作为早期发生 动脉粥样硬化，溶酶体脂质积累可能非常重要 在疾病进展中。 超微结构定量的综合使用 脂质生物化学将提供对 这个早期事件的机制，反过来将有助于更好地定义 这个早期事件的机制，反过来将有助于更好地定义 动脉粥样硬化病变进展的过程。 此外，研究 可以为可能的早期治疗方式提供重要的线索。