CAUSES & TREATMENT OF PRIMARY HYPERCHOLESTEROLEMIA

原因

• 批准号: 3485964
• 负责人: Scott M. Grundy
• 金额: $ 42.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3485964
• 关键词: aging; analytical ultracentrifugation; antihypercholesterolemic agent; antihyperlipoproteinemic agent; apolipoproteins; blood chemistry; blood lipoprotein metabolism; cardiovascular disorder chemotherapy; cardiovascular disorder diagnosis; cardiovascular imaging /visualization; cellular pathology; cerebrotendinous xanthomatosis; cholanate compound; cholesterol; cholesterol ester storage disease; cholestyramine; chylomicrons; clofibrate; combination chemotherapy; coronary disorder; diet therapy; dietary carbohydrates; dietary lipid; disease /disorder proneness /risk; electrofocusing; familial hyperlipoproteinemia; familial hyperlipoproteinemia type II; familial hyperlipoproteinemia type III; feces analysis; fibroblasts; gas chromatography; gel electrophoresis; human population genetics; human subject; hypercholesterolemia; hyperlipidemia; hyperlipoproteinemia; hypertriglyceridemia; immunologic techniques; lecithin cholesterol acyltransferase deficiency; ligands; lipid transport; lipogenesis inhibitor; lipoprotein disorder; lovastatin; low density lipoprotein; macrophage; neomycin; nicotinate; nucleic acid sequence; nutrition related tag; obesity; radiotracer; receptor; reducing diet; sitosterols; steroid metabolism disorder; thin layer chromatography; triglycerides; unsaturated fats; very low density lipoprotein

This proposal will examine the causes of primary hypercholesterolemia (nonfamilial hypercholesterolemia), and it will develop a step-care approach to therapy of this condition. One hundred and sixty patients with primary hypercholesterolemia will be studied. They will first be studied by isotope-kinetic techniques to determine their underlying physiological defect, whether decreased receptor-mediated clearance of LDL, reduced affinity of LDL for receptors, or overproduction of LDL. Family studies will be carried out to determine whether the hypercholesterolemia in some families is inherited as a monogenic disorder. If evidence is obtained for the latter, the underlying metabolic defect will be sought, namely, an abnormality in the primary structure of apolipoprotein B, a reduced ability of cells to generate LDL receptors, an overabsorption of cholesterol, a decreased synthesis of bile acids, or a failure to catabolize saturated fatty acids. In patients with overproduction of LDL, several studies will be done including the composition and lipoprotein content of apolipoprotein E, the interaction of VLDL with cells in culture (fibroblasts and macrophages), and the physical characteristics of LDL. Patients with primary hypercholesterolemia will then enter into a treatment program. The first phase will be diet in which the effectiveness of diets low in fat and high in monounsaturated fats will be compared. The next step will be to study the additional benefit from drugs used in low doses to inhibit the absorption of cholesterol (sitostanol) and bile acids (cholestyramine). Finally, these regimens will be compared to HMG CoA reductase inhibitors (mevinolin). As a last study, the mechanisms of action of mevinolin and cholestyramine will be compared in patients with reduced clearance of LDL, while mevinolin and nicotinic acid will be compared in patients with overproduction of LDL.

该建议将审查主要的原因 高胆固醇血症（非家庭高胆固醇血症），它 将开发一种对这种情况治疗的步骤护理方法。 一百六十例原发性高胆固醇血症患者 将被研究。 他们将首先通过同位素运动研究 确定其潜在生理缺陷的技术， 是否减少了受体介导的LDL清除率，还原 LDL对受体的亲和力或LDL的生产过多。 家庭 将进行研究以确定是否 某些家庭中的高胆固醇血症被遗传为单基因 紊乱。 如果获得了后者的证据 将寻求代谢缺陷，即 载脂蛋白B的一级结构，细胞的能力降低 产生LDL受体，胆固醇的吸收过度，A 胆汁酸的合成降低或未能分解代谢 饱和脂肪酸。 在LDL生产过多的患者中 将完成几项研究，包括组成和 载脂蛋白E的脂蛋白含量，VLDL的相互作用 培养细胞（成纤维细胞和巨噬细胞），以及 LDL的物理特征。 主要患者 然后，高胆固醇血症将进入治疗计划。 第一阶段将是饮食饮食的有效性低 在脂肪中，将比较单不饱和脂肪的高脂肪。 这 下一步将是研究所用药物的额外好处 低剂量以抑制胆固醇的吸收（Sitostanol） 和胆汁酸（胆胺）。 最后，这些方案将是 与HMG COA还原酶抑制剂（甲醇蛋白）相比。 最后 研究，甲醇蛋白和胆碱胺的作用机理 将在LDL清除率降低的患者中比较 虽然将在患者中比较梅维诺素和烟酸 LDL生产过多。