BIOCHEMICAL GENETICS OF CELLULAR CHOLESTEROL METABOLISM

血清胆固醇水平的调节缺陷在 在动脉粥样硬化的发展中的作用，动脉粥样硬化的主要原因 死亡率在美国。 调节细胞和 器官胆固醇稳态假设涉及 一种或多种含氧甾醇，其作为信号调节 胆固醇代谢的许多方面，包括合成和 受体介导的清除。 在本建议中，我们描述 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的机制， 含氧甾醇对培养细胞甾醇代谢的影响 哺乳动物细胞 还提出了实验来确定 环氧甾醇的合成和功能机制与 调节固醇代谢。 这些后一种化合物已被 发现天然存在于人类肝脏中， 被证明具有重要的细胞功能。 最后 提出了一系列的实验来研究的机制， 氧化甾醇对肝脏胆固醇的调节作用 新陈代谢. 预计这些研究将有助于 发展化学治疗方法， 动脉粥样硬化，以及提供新的光对可能的 环氧甾醇的功能。

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.