CELLULAR CHOLESTEROL MOVEMENT AND HOMEOSTATSIS

描述(摘自申请者摘要)：细胞胆固醇是 普遍关注，因为它对健康造成了巨大的负担 动脉粥样硬化性心血管疾病。我们现在建议继续我们的 细胞胆固醇动态平衡的研究。假设这个池中的 质膜中的胆固醇通过信号调节自身的丰度 内质网(ER)通过流的调节循环 胆固醇的含量将会被检测。假定胆固醇的设定值 将传感器置于质膜中进行表征。 调查人员还将测试高尔基体中的胆固醇池 仪器由质膜传感器调节；也许高尔基体 在胆固醇运输中起中间体的作用。等离子体的通量 通过溶酶体的膜胆固醇将使用来自 Niemann-Pick C1型(NPC1)病及不同药物对细胞的作用 扰乱胆固醇新陈代谢的两亲分子。问题是，是否 这种运动代表了大量等离子体的特定运输或流动。 将讨论膜双分子层。NPC1基因产物似乎是 与胆固醇稳态有关。调查人员将分析它是如何 其表达随细胞胆固醇的不同而不同。最后，人体的细胞生理学 将对NPC1中的几个测序突变进行基因分析 缺陷是研究NPC1如何在胆固醇稳态中发挥作用。

DESCRIPTION (Adapted from applicant's abstract): Cell cholesterol is of universal concern because of the enormous burden on health imposed by atherosclerotic cardiovascular disease. We now propose to continue our study o cellular cholesterol homeostasis. The hypothesis that the pool of cholesterol in the plasma membrane regulates its own abundance by signaling the endoplasmi reticulum (ER) through the regulated circulation of a stream of cholesterol will be tested. The set point of a putative cholesterol sensor in the plasma membrane will be characterized. The investigators will also test whether the cholesterol pool in the Golgi apparatus is regulated by the plasma membrane sensor; perhaps the Golgi serves as an intermediate in cholesterol transport. The flux of plasma membrane cholesterol through the lysosomes will be analyzed using cells from Niemann-Pick type C1 (NPC1) disease and cells treated with various amphiphiles which perturb cholesterol metabolism. The question of whether this movement represents specific transport or the flow of bulk plasma membrane bilayer will be addressed. The NPC1 gene product appears to be involved in cholesterol homeostasis. The investigators will analyze how its expression varies with cel cholesterol. Finally, the cell physiology of several sequenced mutants in NPC1 will be analyzed with respect to the gene defect to examine how NPC1 might function in cholesterol homeostasis.