Nanoscale Engineering of LDL-Retentive Substrates

LDL 保留基质的纳米工程

• 批准号: 0201788
• 负责人: Prabhas Moghe
• 金额: $ 29.7万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0201788&HistoricalAwards=false
• 关键词: Nanoscale; Engineering; LDL; Retentive; Substrates

0201788MogheCardiovascular disease takes a staggering toll of casualties among adult Americans each year. Two of the significant vascular pathologies related to the abnormal accumulation of lipids are atherosclerosis (the hardening of arteries due to build-up of low density lipoproteins (LDL)), and macrovascular disease, typically correlated with insulin resistant diabetes, which claims a million lives each year globally. Much research has been directed at the molecular design of drugs to alleviate the disorders of lipid metabolism. However, such drugs can be toxic to the liver and kidneys, and fail to comprehensively treat lipoprotein transport and retention dynamics, particularly at peripheral vascular sites. Thus, a comprehensive approach to treating lipid-related vascular disease could involve use of molecules regulating lipid metabolism as well as molecules that are suitably lipoprotein-philic and serve as multifunctional carriers for processing lipoproteins in transit. Ultimately, such carriers could be engineered to (a) sequester lipoproteins from macromolecular depots such as proteoglycans that heighten atherogenic tendencies; (b) reduce lipoprotein oxidation (which leads to unregulated uptake of LDL by macrophages, transforming them into foam cells, the precursors to atherosclerosis); and (c) enhance lipoprotein transport and clearance of mildly oxidized lipoproteins (via macrophages, and the liver). However, to engineer such carriers, an understanding of the chemical and geometric determinants of lipoprotein-retentive carrier substrates is necessary. This proposal describes a major research initiative toward this goal.The proteoglycans of the vascular intima are bulky, negatively charged molecules that present multimeric glycosaminoglycan (GAG) chains, which can co-operatively recruit low density lipoproteins, and encourage LDL hyperoxidation, which leads to foam cell formation during atherosclerosis. As a competitive strategy for LDL retention, the investigators propose to design novel diffusible, nanoscale carriers that can present GAG-mimetic chemistry and retain LDL with high affinity. To this end, two significant questions will be addressed: (a) Can the GAG-mimetic chemistry and nanoscale topography of model substrates be designed to synergistically recruit oxidized low density lipoproteins? (b) How can the insights derived in (a) be applied toward the use of mobile nanocarriers for LDL retention?To address (a), the investigators will theoretically simulate and experimentally explore the ability of immobilized gold nanoparticles (model substrates to test the LDL-reactivity of various chemistries) and substrate arravs of gold/ZnO nanopillars. functionalized with alkanethiols terminating in negatively charged groups (-COOH, -OSO3H), to sequester LDL. The hypothesis is that at adequately high densities, and in topographic substrate configurations affording inter-pillar cooperativity, such chemistries can electrostatically sequester LDL through the positively charged aminoacid residues from the apolipoprotein B-100 of the LDL. To address (b), the investigators will explore the use of polymeric dendrimer-Iike hyperbranched nanocarriers to present the most LDL-retentive chemistry observed in (a), in various nanoarchitectural configurations, that is, by systematically manipulating the valency, branching, and tethering of the molecular bait for the lipoprotein.

心血管疾病每年在美国成年人中造成惊人的伤亡。与脂质异常积累相关的两种重要的血管病理是动脉粥样硬化（由于低密度脂蛋白（LDL）的积聚导致的动脉硬化）和大血管疾病，其通常与胰岛素抵抗性糖尿病相关，其每年在全球夺去一百万人的生命。许多研究已经针对减轻脂质代谢紊乱的药物的分子设计。然而，这类药物可能对肝脏和肾脏有毒，并且不能全面治疗脂蛋白转运和保留动力学，特别是在外周血管部位。因此，治疗脂质相关血管疾病的综合方法可能涉及使用调节脂质代谢的分子以及适当亲脂蛋白并用作转运中处理脂蛋白的多功能载体的分子。最终，这些载体可以被改造为（a）从大分子库如蛋白聚糖中隔离脂蛋白，所述大分子库提高致动脉粥样硬化倾向;（B）减少脂蛋白氧化（这导致巨噬细胞对LDL的不受调节的摄取，将它们转化为泡沫细胞，动脉粥样硬化的前体）;和（c）增强脂蛋白转运和轻度氧化脂蛋白的清除（通过巨噬细胞和肝脏）。然而，工程这样的载体，脂蛋白滞留载体基板的化学和几何决定因素的理解是必要的。 血管内膜的蛋白多糖是一种大的、带负电荷的多聚体糖胺聚糖（GAG）链，它可以协同募集低密度脂蛋白，促进LDL过氧化，导致动脉粥样硬化过程中泡沫细胞的形成。作为LDL保留的竞争策略，研究人员建议设计新的可扩散的纳米级载体，可以呈现GAG模拟化学并以高亲和力保留LDL。为此，两个重要的问题将得到解决：（a）可以GAG模拟化学和纳米级拓扑结构的模型基板被设计为协同招聘氧化低密度脂蛋白？(b)如何将（a）中得出的见解应用于使用移动的纳米载体来保留LDL？为了解决（a），研究人员将在理论上模拟和实验上探索固定化金纳米颗粒（用于测试各种化学品的LDL反应性的模型基底）和金/ZnO纳米柱的基底阵列的能力。用以带负电荷的基团（-COOH、-OSO 3 H）封端的烷硫醇官能化，以螯合LDL。假设是在足够高的密度下，并且在提供柱间协同性的地形基质配置中，这种化学物质可以通过来自LDL的载脂蛋白B-100的带正电荷的氨基酸残基静电螯合LDL。为了解决（B），研究者将探索使用聚合物树状聚合物样超支化纳米载体来呈现（a）中观察到的最具LDL保留性的化学，以各种纳米结构构型，即，通过系统地操纵脂蛋白的分子诱饵的化合价、分支和拴系。