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，一种血管壁的慢性炎症性疾病，在西方国家占所有死亡的近50%，是糖尿病患者死亡的主要原因。该提案利用合理的分子设计方法来开发一类新的治疗剂-用作动脉粥样硬化保护和抗炎治疗剂的两亲性聚合物。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，在动脉粥样硬化形成的早期阶段，通过多个清道夫受体靶向和阻断。这种结合行为对于阻断氧化LDL摄取和更有效地消除动脉粥样硬化炎症级联反应以及延缓动脉粥样硬化的进展可能是至关重要的。关于增强的聚合物结构的中心假设是，增强的疏水特征与阴离子电荷和亲水尾部的组合将产生具有最佳靶向巨噬细胞和内皮细胞上的多种清道夫受体（特别是SR-A、CD 36和LOX-1）的聚合物。为了检验这一假设，提出了三个具体目标。目的1是集中在分子建模（对接和评分）和设计新的聚合物类增强结合多种清道夫受体。这一努力将产生新的聚合物结构，具有更刚性和空间填充骨架，结合电荷和亲水性，增强对清道夫受体的结合亲和力-特别是在生理条件下。目的二是研究高分子材料抑制动脉粥样硬化炎症的分子机制及其与巨噬细胞和内皮细胞的相互作用。目的3集中于使用加速动脉粥样硬化的动物模型在结合动脉粥样硬化病变和动脉粥样硬化炎症标志物消退程度方面评价体内聚合物功效。最低限度，将获得新的见解，关于多种清道夫受体阻断作为一种策略，以抵消动脉粥样硬化的进展。这项研究提案的潜在影响很大;总体结果可能是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。 公共卫生相关性：该项目涉及具有生物活性和抗动脉粥样硬化功效的聚合物生物材料的设计，动脉粥样硬化是导致心脏病发作和中风的脂质（脂肪）填充血管的渐进性阻塞，这是美国成年人死亡的主要原因。以及鉴定改进的可生物降解的聚合物材料作为治疗血管和炎性疾病的治疗剂。

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. PUBLIC HEALTH RELEVANCE: This project is concerned with the design of polymeric biomaterials with biological activity and efficacy against atherosclerosis, the progressive blockage of lipid (fat) filled blood vessels leading to heart attacks and strokes, a leading cause of adult mortality in the U.S. Outcomes will be insights into the structure-function relations between polymers and their blockage of cholesterol uptake; effects on inhibition of inflammation; and the identification of improved biodegradable polymeric materials as therapeutics for treatment of vascular and inflammatory diseases.