BIOCHEMICAL GENETICS OF CELLULAR CHOLESTEROL METABOLISM

对血清胆固醇水平的有缺陷的调节起着关键作用 在动脉粥样硬化发展中的作用，动脉粥样硬化的主要原因 美国的死亡率。对细胞和细胞的调节 据推测，生物体的胆固醇稳态与 一种或多种含氧的甾醇，起到调节 胆固醇代谢的一些方面，包括合成和 受体介导的清除。在这份提案中，我们描述了 利用分子和体细胞相结合的实验 基因技术旨在进一步阐明疾病的机制 含氧甾醇对体外培养的人胚乳中甾醇代谢的影响 哺乳动物细胞。还建议进行实验，以确定 与之无关的环氧甾醇的合成和功能机制 类固醇代谢的调节。这些后一种化合物已经被 被发现天然存在于人的肝脏中，并已被 被证明具有重要的细胞功能。最后，一个 提出了一系列实验来检验这些机制。 氧化甾醇在肝脏胆固醇调节中的作用 新陈代谢。预计这些研究将有助于 化疗方法的进展及其对治疗的影响 动脉粥样硬化以及可能的 环氧甾醇的作用。

Defective regulation of serum cholesterol levels plays a critical role in the development of atherosclerosis, the leading cause of mortality in the United States. Regulation of cellular and organismic cholesterol homeostasis has been hypothesized to involve one or more oxygenated sterols which act as a signal regulating a number of aspects of cholesterol metabolism including synthesis and receptor mediated clearance. In this proposal, we describe experiments utilizing a combination of molecular and somatic cell genetic techniques designed to further elucidate the mechanisms of action of oxygenated sterols on sterol metabolism in cultured mammalian cells. Experiments are also proposed to determine mechanisms of synthesis and function of epoxysterols unrelated to regulation of sterol metabolism. These latter compounds have been found to be naturally occurring in human liver and have been demonstrated to perform a vital cellular function. Finally, a series of experiments are proposed to examine the mechanisms of action of oxysterols in the regulation of hepatic cholesterol metabolism. It is anticipated that these studies will aid in the development of chemotherapeutic methods towards management of atherosclerosis as well as shedding new light on the possible function of epoxysterols.