Enhanced Hepatic Lipoprotein Uptake and Atherogenesis

描述(申请人提供)：降低血浆胆固醇可降低 患冠心病的风险。降低血浆浓度的一般方法 胆固醇是为了增加受体，加速人体的分解代谢。 肝摄取致动脉粥样硬化性脂蛋白。我们提出了一个 增加含载脂蛋白B的脂蛋白分解代谢的替代方法；即， 在循环中加入与LP表面结合的小肽，并 确保其快速、有针对性地输送到肝脏，从循环中移除 远离外围。为了实现这一点，我们设计了多肽 包含高效磷脂结合结构域和 将这个脂蛋白靶向结构域连接到载脂蛋白E的富含Arg的结构域上 允许与受体和细胞表面蛋白多糖相互作用。 这里提供的初步数据表明，其中一种多肽确实具有这些 并显著降低血浆总胆固醇(TC)水平 载脂蛋白E(-/-)小鼠动脉粥样硬化模型，不依赖于多肽途径 送货。此外，这种多肽在两年内显著而迅速地降低了TC 其他小鼠模型，载脂蛋白E(-/)//低密度脂蛋白-R(-/-)和胆固醇喂养的C57BL/6 老鼠。这种降低血浆总胆固醇的替代方法可能是最有效的 在受体缺陷的血脂异常的受试者中。进一步发展和发展 为了理解这些现象，我们提出了两个具体目标。La)来描述 控制Lp结合的这些多肽的最低结构要求 和肝脏清除致动脉粥样硬化的脂蛋白，b)确定分子 多肽介导致动脉粥样硬化脂蛋白结合和摄取机制的研究 受体缺陷和蛋白多糖缺陷细胞系以及肝细胞 来自动脉粥样硬化小鼠模型。2)。测定…的体内代谢 多肽对小鼠致动脉粥样硬化脂蛋白的清除作用 动脉硬化。产生的数据将提供分子基础和 对使用必要的替代策略降低高位的理解 血浆胆固醇水平。这也将为设计提供合理的依据 和提供多肽模拟物及其在治疗中的治疗用途 动脉粥样硬化。

DESCRIPTION (provided by applicant): Lowering plasma cholesterol lowers the risk of coronary heart disease. A general approach to lowering plasma cholesterol is to increase receptors that accelerate the catabolism of the atherogenic lipoproteins (Lps) througi iepatic uptake. We propose an alternative method to increase the catabolism of apo B-containing Lps; that is, adding a small peptide to the circulation that binds to the Lp surface and ensures its rapid, targeted delivery to the liver for removal from circulation and away from the periphery. To accomplish this, we have designed peptide mimetics that contain a highly efficient phospholipid-binding domain and attached this lipoprotein targeting domain to an Arg-rich domain of apo E that allows putative interaction with receptors and cell-surface proteoglycans. Preliminary data presented here indicate that one such peptide indeed has these properties and dramatically reduce plasma total cholesterol (TC) levels in the apo E (-/-) mouse model of atherosclerosis, independent of the route o peptide delivery. In addition, this peptide lowered TC dramatically and rapidly in two other mouse models, the apo E(-/)//LDL-R(-/-) and the cholesterol-fed C57BL/6 mouse. This alternative method for lowering plasma TC might be most efficacious in subjects with receptor-defective dyslipidemias. To further develop and understand these phenomena we propose two specific aims. la) To characterize the minimum structural requirements of these peptides that control Lp binding and hepatic removal of atherogenic lipoproteins, b) to determine the molecular mechanisms of peptide-mediated binding and uptake of atherogenic Lps using receptor-defective and proteoglycan-deficient cell lines as well as hepatocytes from atherosclerosis mouse models. 2). To determine the in viw metabolism of the peptide-mediated removal of atherogenic lipoproteins in murine models of atherosclerosis. The data generated will provide the molecular basis and understanding for the use of needed alternative strategies o lowering high plasma cholesterol levels. It will also provide a rational basis for the design and delivery of peptide mimetics and for their therapeutic use in the treatment of atherosclerosis.