Cholesterol Regulation of Lysosomes

项目摘要 这项研究的长期目标是了解胆固醇是如何增加的。 进入蜂窝内隔间以供使用、存储和蜂窝 通过两种糖蛋白：NPC1和LAMP蛋白进行调节。NPC1需要用于 内吞的低密度脂蛋白衍生的胆固醇从溶酶体流出到 细胞质。LAMP蛋白是构成限制因子的主要糖蛋白。 溶酶体膜。这个应用程序的目标是研究这些 蛋白质可能协作将胆固醇从溶酶体中转移出来，使用 生物化学和细胞生物学方法。建议进行实验，以 进一步研究这些蛋白质之间依赖胆固醇的相互作用， 以及它们和它们的相互作用如何影响下游的激活 溶酶体生物发生。这些实验将提供重要的信息 关于细胞如何感知和信号传递胆固醇在体内的可用性 溶酶体，并从溶酶体输出胆固醇。这项工作具有重要的意义 对包括心血管疾病在内的许多疾病状态的影响， 癌症和神经性疾病。

Project Summary The long term goal of this research is to understand how cholesterol gains access to intracellular compartments for utilization, storage and cellular regulation, via two glycoproteins: NPC1 and LAMP proteins. NPC1 is needed for the egress of endocytosed, LDL-derived cholesterol from lysosomes into the cytoplasm. LAMP proteins constitute the major glycoproteins that line the limiting membranes of lysosomes. The goal of this application is to study how these proteins may cooperate to transport cholesterol out of lysosomes, using biochemical and cell biological approaches. Experiments are proposed to investigate further, the cholesterol-dependent interaction between these proteins, and how they, and their interactions, may influence downstream activation of lysosome biogenesis. These experiments will provide important information regarding how cells may sense and signal the availability of cholesterol in lysosomes, and export cholesterol from lysosomes. This work has important implications for a number of disease states including cardiovascular disease, cancer, and neurological disorders.