Synthetic Counter-ligands for Inhibition of Atherosclerosis

描述（由申请人提供）：本研究针对动脉粥样硬化，这是一种慢性血管壁炎症性疾病，在西方国家造成近50%的死亡，是糖尿病患者死亡的主要原因。该建议利用合理的分子设计方法来研究一类新的治疗药物-两亲性聚合物，作为动脉粥样硬化保护和抗炎治疗药物。最具创新性的部分是，分子设计的聚合物可能具有抑制动脉粥样硬化的潜力，通过多种清道夫受体靶向和阻塞动脉粥样硬化的早期阶段。这种结合行为对于阻断氧化LDL的摄取，更有效地消除动脉粥样硬化-炎症级联反应，延缓动脉粥样硬化的进展至关重要。关于增强聚合物结构的核心假设是，将增强的疏水特性与阴离子电荷和亲水尾部结合在一起，将产生针对巨噬细胞和内皮细胞上的多种清道夫受体（特别是SR-A， CD36和LOX-1）的最佳靶向聚合物。为了验证这一假设，提出了三个具体目标。目标1的重点是分子建模（对接和评分）和新型聚合物类的设计，以增强与多种清道夫受体的结合。这一努力将产生新的聚合物结构，具有更刚性和更充满空间的骨架，结合电荷和亲水性，增强与清道夫受体的结合亲和力-特别是在生理条件下。目的2是研究体外培养巨噬细胞和内皮细胞抑制动脉粥样硬化炎症的分子机制和聚合物相互作用。Aim 3的重点是利用加速动脉粥样硬化的动物模型，评估体内聚合物与动脉粥样硬化病变结合的功效以及动脉粥样硬化炎症标志物的消退程度。至少，将获得关于多种清道夫受体阻断作为对抗动脉粥样硬化进展的策略的新见解。本研究计划的潜在影响很大；总的结果可能是一种治疗冠状动脉疾病的新方法——使用增强聚合物作为多功能抑制剂。

DESCRIPTION (provided by applicant): This study targets atherosclerosis, a chronic inflammatory disorder of the blood vessel wall, which underlies nearly 50% of all deaths in westernized countries and is the primary cause of mortality in patients with diabetes. This proposal utilizes rational molecular design approaches to a novel class of therapeutics - amphiphilic polymers that serve as athero-protective and anti-inflammatory therapeutics. The most innovative component is that molecularly designed polymers may have the potential to inhibit atherosclerosis by multiple scavenger receptor targeting and blockage during the early stages of atherogenesis. This binding behavior could be critical to blocking oxidized LDL uptake and more effectively abrogate the athero-inflammatory cascade, and retard the progression of atherosclerosis. The central hypothesis regarding the enhanced polymer structures is that combinations of strengthened hydrophobic features in conjunction with anionic charge and hydrophilic tails will yield polymers with optimal targeting to multiple scavenger receptors on both macrophages and endothelial cells, specifically SR-A, CD36 and LOX-1. To test this hypothesis, three specific aims are proposed. Aim 1 is focused on the molecular modeling (docking and scoring) and design of novel polymer classes for enhanced binding to multiple scavenger receptors. This effort will yield new polymer structures with a more rigid and space-filling backbone that, in conjunction with charge and hydrophilicity, enhance binding affinities to scavenger receptors - particularly under physiologic conditions. Aim 2 is focused on investigating the molecular mechanisms and polymer interactions with cultured macrophages and endothelial cells for inhibition of athero-inflammation in vitro. Aim 3 is focused on the evaluation of in vivo polymer efficacy in terms of binding to atherosclerotic lesions and degree of regression of athero-inflammatory markers using an animal model of accelerated atherosclerosis. At minimum, new insights will be obtained regarding multiple scavenger receptor blocking as a strategy to counteract the progression of atherosclerosis. The potential impact of this research proposal is high; the overall outcome may be a new approach to treating coronary artery disease - using enhanced polymers as multifunctional inhibitors.