LYSOSOMES AND ATHEROSCLEROTIC FOAM CELL GENESIS

在动脉粥样硬化的特定重要阶段，泡沫细胞积聚 大的肿胀的溶酶体内的胆固醇。 大量研究 这表明了这种现象在发病机制中的重要性。 疾病，但这种溶酶体积累的原因是未知的。 长 我们研究的长期目标是了解这两种机制， 溶酶体脂质充盈在动脉粥样硬化形成中重要性 的 在本申请中提出的实验将通过以下方式探索该机制： 从而发生溶酶体脂质积累。 在这些研究中，2 脂蛋白将用于将胆固醇装载到细胞中。 1（ox-LDL） 促进胆固醇（ox-LDL）的显著溶酶体积累， 另一种胆固醇（ac-LDL）似乎可以有效地从 溶酶体并在细胞质内含物内积累。 我们将比较 从这两种脂蛋白中代谢胆固醇， 它们的存储模式发生了变化。 这涉及 将脂质蓄积的定量超微结构数据与 溶酶体和细胞质内含物对胆固醇生化指标的影响 代谢和积累。 具体来说，我们将确定 细胞转运程度，溶酶体水解，细胞质 再酯化、细胞质水解和细胞胆固醇流出 在溶酶体蓄积中发挥作用。 作为一个早期的事件， 在动脉粥样硬化形成中，溶酶体脂质积聚可能非常重要 在疾病进展中。 超微结构定量的综合应用 和脂质生物化学将提供一个详细的了解， 这一早期事件的机制，反过来，将有助于更好地确定 这一早期事件的机制，反过来，将有助于更好地确定 动脉粥样硬化病变进展的过程。 此外，研究 可以为早期治疗提供重要线索。

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.