METABOLISM OF A SYNTHETIC ANTI-ATHEROGENIC LIPOPROTEIN

合成抗动脉粥样硬化脂蛋白的代谢

• 批准号: 3471460
• 负责人: Kevin Jon Williams
• 金额: $ 5.91万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1989-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471460
• 关键词: antiatherogenic agent; aorta; apolipoproteins; atherosclerosis; blood lipoprotein metabolism; cardiovascular disorder chemotherapy; cholesterol; cholestyramine; drug vehicle; gel electrophoresis; gel filtration chromatography; histopathology; laboratory rabbit; lipid transport; liposomes; liver function; lovastatin; low density lipoprotein; macrophage; neoplastic cell culture for noncancer research; nutrition related tag; phospholipids; radiotracer; receptor mediated endocytosis; scintillation cameras; tissue /cell culture; very low density lipoprotein; whole body radionuclide scanning

The overall objective of this research is to determine the mechanism by which phospholipid infusions produce rapid, substantial regression of experimental atherosclerosis. This knowledge will allow rational modifications in the treatment and may eventually allow its application to the human disease. The present proposal will focus on the metabolism of infused phospholipid vesicles. Under the proper circumstances, these particles persist in the circulation for hours, acquire large amounts of endogenous cholesterol and apolipoprotein-E, and appear to be gradually taken up by the liver. Initial studies will be in three areas. First, to explore the mechanism by which vesicles may transport cholesterol from the periphery to the liver, the role of hepatic LDL receptors in hepatic uptake of vesicular particles will be determined. Hepatic clearance will be measured in rabbits with stimulated, suppressed, saturated, or absent hepatic LDL receptors. Second, because vesicles block the ability of B-VLDL, and atherogenic lipoprotein, to cholesterol-load cultured macrophages, blockage of B-VLDL uptake by aortic macrophages will be measured in vivo. Aortic uptake of 125 I-dilactitol tyramine-labeled B-VLDL will be compared in phospholipid-infused and saline-infused animals. Third, the abilities of infused vesicles of different size and composition to acquire endogenous cholesterol, to undergo hepatic clearance, and to block macrophage uptake of B-VLDL will be compared. Subsequent studies will depend on the results of these initial studies. If hepatic LDL receptors are found to be involved in hepatic uptake of vesicular particles, agents that stimulate hepatic LDL receptors will be examined for their ability to accelerate phospholipid-induced regression of atherosclerosis. Conversely, if substantial hepatic uptake of vesicles occurs in the absence of hepatic LDL receptors, the alternate pathways for uptake will be investigated in vitro. Also, the ability of phospholipid infusions to prevent or reverse atherosclerosis in receptor-deficient rabbits will be determined. This last study will be of particular interest, because atherosclerosis in receptor- deficient rabbits closely resembles the human disease in histology and anatomic distribution. The ultimate goal is a rational, non-invasive treatment that produces regression of atherosclerosis in humans.

本研究的总体目标是确定 磷脂输注产生快速、 实验性动脉粥样硬化显着消退。 这 知识将允许对治疗进行合理的修改 最终可能会使其应用于人类疾病。 这 目前的提案将重点关注输液的新陈代谢 磷脂囊泡。 在适当的情况下，这些 颗粒在循环中持续数小时，获得大 内源性胆固醇和载脂蛋白-E的量，以及 似乎逐渐被肝脏吸收。 初步研究将集中在三个领域。 首先，要探索 囊泡转运胆固醇的机制 肝脏外周，肝脏 LDL 受体的作用 将测定肝脏对囊泡颗粒的摄取。 肝的 将在刺激、抑制、 肝脏 LDL 受体饱和或缺失。 其次，因为 囊泡阻断 B-VLDL 和致动脉粥样硬化脂蛋白的能力， 对胆固醇负荷培养的巨噬细胞，阻断 B-VLDL 将在体内测量主动脉巨噬细胞的摄取。 主动脉 125 I-二乳糖醇酪胺标记的 B-VLDL 的摄取将 在注射磷脂和注射盐水的动物中进行比较。 三、不同大小、不同囊泡的输注能力 获得内源性胆固醇的组合物，经过肝脏 清除，并阻止巨噬细胞摄取 B-VLDL 将 比较的。 后续研究将取决于这些初步结果 研究。 如果发现肝脏 LDL 受体参与 肝脏摄取囊泡颗粒，刺激剂 将检查肝脏 LDL 受体的能力 加速磷脂诱导的动脉粥样硬化的消退。 相反，如果肝脏对囊泡的大量摄取发生在 肝脏低密度脂蛋白受体的缺失，替代途径 将在体外研究吸收。 另外，有能力 输注磷脂可预防或逆转动脉粥样硬化 将确定受体缺陷的兔子。 最后一项研究将 特别令人感兴趣，因为受体中的动脉粥样硬化 缺陷兔子在组织学上与人类疾病非常相似 和解剖分布。 最终目标是合理的、非侵入性的治疗 使人类动脉粥样硬化消退。