NOVEL INHIBITORS OF CHOLESTEROL BIOSYNTHESIS

新型胆固醇生物合成抑制剂

• 批准号: 3337143
• 负责人: THOMAS A SPENCER
• 金额: $ 15.27万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-08-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3337143
• 关键词: antihypercholesterolemic agent; atherosclerosis; binding proteins; diol; hydroxycholesterols; laboratory rat; lanosterol; liver; radioimmunoassay; squalene; steroid biosynthesis; tissue /cell culture; triterpenes

Research will be continued to gain further understanding of the biochemistry of 24(S),25-epoxycholesterol and other oxygenated sterols. Recent evidence has been obtained that this epoxy sterol occurs naturally in human liver tissue and in cultured cells, that it represses HMG-CoA reductase activity, and that it binds to the cytosolic oxysterol binding protein. These findings suggest that 24(S),25-epoxycholesterol is a natural regulator of cholesterol formation. Further efforts will be directed toward gaining direct evidence for such a regulatory role for this epoxide and other oxysterols. Included will be determination of the incidence of epoxy sterols and other oxysterols in additional media selected to elucidate a regulatory role. Evidence will be sought that the concentration of cellular oxysterols changes as a function of a change in HMG-CoA reductase activity. The biosynthesis of 25-hydroxycholesterol will be elucidated and the metabolic fate of that compound and of 24(S),25-epoxycholesterol will be determined. Other experiments will be conducted to determine if 24(S),25-epoxycholesterol or other substances derived from squalene dioxide have additional diochemical importance. Effort will also be expended to develop photoaffinity labels to assist in characterization of two important enzymes involved in sterol biochemistry, the oxysterol binding protein and oxidosqualene cyclase. Additional prospective late-stage inhibitors of cholesterol biosynthesis will be prepared and evaluated. Attempts will be made to develop a radioimmunoassay for mevalonic acid. All of these planned experiments have as their fundamental goal a better understanding of the mechanism of cholesterol regulation. Such an understanding will eventually be important in achieving control of atherosclerosis, and the results may have implications for control of tumor cell growth as well.

研究将继续进一步了解 24（S），25-钙胆固醇和其他氧化固醇的生物化学。 最近有证据表明这种环氧固醇自然发生 在人肝组织和培养细胞中，它抑制了HMG-COA 还原酶活性，并与胞质氧结合结合 蛋白质。 这些发现表明24（s），25-蛋白胆固醇是一个 胆固醇形成的天然调节剂。 将进一步努力 致力于获得这种调节作用的直接证据 环氧化物和其他氧化甲醇。 其中包括的是确定 其他培养基中的环氧固醇和其他氧化酚的发生率 被选为阐明调节作用。 将寻求证据表明 细胞氧蛋白酶的浓度随着变化的变化而变化 HMG-COA还原酶活性。 25-羟基胆固醇的生物合成将 阐明该化合物和该化合物的代谢命运 将确定24（s），25-蛋白胆固醇。 其他实验将是 进行以确定24（s），25-蛋白胆固醇或其他物质是 源自二氧化孢子的二氧化物具有额外的二元化重要性。 还将努力开发光性标签以帮助 涉及固醇生物化学的两种重要酶的表征， 氧化酚结合蛋白和氧化盐环酶。 额外的 胆固醇生物合成的前期晚期抑制剂将是 准备和评估。 将尝试开发 甲酸甲酸的放射免疫分子。 所有这些计划的实验都有 作为他们的基本目标，可以更好地理解 胆固醇调节。 这样的理解最终将很重要 在控制动脉粥样硬化时，结果可能具有 也对控制肿瘤细胞生长的影响。