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: 3471463
• 负责人: Kevin Jon Williams
• 金额: $ 13.75万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 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 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471463
• 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.

这项研究的总体目的是确定 磷脂输注产生迅速的机制， 实验性动脉粥样硬化的大量消退。 这 知识将允许治疗中的理性修改和 最终可能允许其应用于人类疾病。 这 目前的建议将重点放在注入的新陈代谢上 磷脂囊泡。 在适当的情况下，这些 颗粒在循环中持续数小时，获取大量 内源性胆固醇和载脂蛋白-E的量，以及 似乎被肝脏逐渐吸收。 初步研究将在三个领域。 首先，探索 囊泡可以从中运输胆固醇的机制 肝脏的外围，肝LDL受体在 将确定肝颗粒的肝摄取。 肝 清除将在具有刺激，抑制的兔子中测量 饱和或没有肝LDL受体。 第二，因为 囊泡阻止B-VLDL和动脉粥样硬化脂蛋白的能力， 胆固醇负载培养的巨噬细胞，B-VLDL的阻塞 主动脉巨噬细胞的摄取将在体内测量。 主动脉 吸收125 i-dilactitol标记的B-VLDL将是 在注入磷脂和盐水的动物中进行了比较。 第三，注入不同大小的囊泡的能力和 获取内源性胆固醇的成分，进行肝 清除，并阻止B-VLDL的巨噬细胞吸收 比较的。 随后的研究将取决于这些初始的结果 研究。 如果发现肝LDL受体参与 肝颗粒的肝摄取，刺激的药物 将检查肝LDL受体的能力 加速磷脂诱导的动脉粥样硬化消退。 相反，如果大量的肝摄取发生在 没有肝LDL受体，这是替代途径 摄取将在体外研究。 另外， 磷脂输注以预防或逆转动脉粥样硬化 将确定受体缺陷型兔子。 最后一项研究将 特别令人感兴趣，因为动脉粥样硬化在受体中 缺乏兔子与组织学上的人类疾病非常相似 和解剖分布。 最终目标是一种理性的，无创的待遇， 产生人类动脉粥样硬化的消退。