Enhanced Hepatic Lipoprotein Uptake and Atherogenesis

描述（由申请人提供）：降低血浆胆固醇可降低 冠心病的风险。降低血浆浓度的一般方法 胆固醇的作用是增加受体，加速 致动脉粥样硬化脂蛋白（LPS）可抑制脂质摄取。我们提出了一个 增加含载脂蛋白B的脂蛋白的催化活性的替代方法;即， 向循环中添加与Lp表面结合的小肽， 确保其快速，有针对性地输送到肝脏，从循环中清除 并且远离外围。为了实现这一点，我们设计了肽 含有高效磷脂结合结构域的模拟物， 将该脂蛋白靶向结构域连接到载脂蛋白E的富含Arg的结构域， 允许与受体和细胞表面蛋白聚糖的假定相互作用。 这里提供的初步数据表明，一种这样的肽确实具有这些特性。 性质，并显着降低血浆总胆固醇（TC）水平， 载脂蛋白E（-/-）小鼠动脉粥样硬化模型，不依赖于肽途径 交付.此外，这种肽在两种情况下显著而迅速地降低了TC。 其他小鼠模型，apo E（-/）//LDL-R（-/-）和胆固醇喂养的C57 BL/6 老鼠.这种降低血浆TC的替代方法可能最有效 受体缺陷型血脂异常的受试者。进一步发展和 了解这些现象，我们提出两个具体目标。（a）描述 控制Lp结合的这些肽的最低结构要求 和肝清除致动脉粥样硬化脂蛋白，B）以确定分子 肽介导的致动脉粥样硬化脂蛋白结合和摄取的机制 受体缺陷和蛋白聚糖缺陷细胞系以及肝细胞 动脉粥样硬化小鼠模型。2）。为了确定体内代谢， 肽介导的致动脉粥样硬化脂蛋白的清除 动脉粥样硬化产生的数据将提供分子基础， 了解使用所需的替代战略， 血浆胆固醇水平为设计提供了合理的依据 以及它们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.