Synthetic Counter-ligands for Inhibition of Atherosclerosis

描述(申请人提供)：这项研究的目标是动脉粥样硬化，这是一种慢性血管壁炎症性疾病，在西化国家占所有死亡人数的近50%，也是糖尿病患者死亡的主要原因。这项建议利用合理的分子设计方法来开发一类新的治疗药物--两亲性聚合物，用作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通过多种清道夫受体靶向和阻断在动脉粥样硬化形成的早期阶段抑制动脉粥样硬化的潜力。这种结合行为可能对阻止氧化的低密度脂蛋白摄取至关重要，并更有效地消除动脉粥样硬化的炎症级联反应，并延缓动脉粥样硬化的进展。关于增强聚合物结构的中心假设是，增强的疏水特性与阴离子电荷和亲水性尾巴相结合，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的聚合物，特别是SR-A、CD36和LOX-1。为了验证这一假设，本文提出了三个具体目标。目标1专注于分子建模(对接和评分)和设计新的聚合物类别，以增强与多种清道夫受体的结合。这一努力将产生具有更坚硬和空间填充主干的新聚合物结构，与电荷和亲水性相结合，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主要研究体外培养的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。目的3利用加速动脉粥样硬化的动物模型，根据与动脉粥样硬化病变的结合和动脉粥样硬化炎症标志物的消退程度来评估聚合物的体内疗效。至少，将获得关于多个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。这项研究提案的潜在影响很高；总体结果可能是一种治疗冠状动脉疾病的新方法--使用增强型聚合物作为多功能抑制剂。 与公共卫生相关：该项目涉及设计具有生物活性和抗动脉粥样硬化功效的聚合物生物材料，该材料可逐渐阻断充满脂质(脂肪)的血管，从而导致心脏病发作和中风，而心脏病发作和中风是美国成年人死亡的主要原因。结果将是深入了解聚合物与其阻断胆固醇吸收之间的结构功能关系；抑制炎症的作用；以及确定改进的可生物降解聚合物材料作为治疗血管和炎症性疾病的疗法。

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.