Synthetic Counter-ligands for Inhibition of Atherosclerosis

抑制动脉粥样硬化的合成反配体

• 批准号: 8087411
• 负责人: PRABHAS V MOGHE
• 金额: $ 61.48万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087411
• 关键词: Address; Adult; Affinity; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Behavior; Behavior Therapy; Binding; Biocompatible Materials; Biological; Biomedical Engineering; Blood Vessels; CD36 gene; Cardiovascular Diseases; Cessation of life; Charge; Cholesterol; Chronic; Clinical; Coronary Arteriosclerosis; Country; Development; Diabetes Mellitus; Disease; Docking; Endothelial Cells; Endothelium; Evaluation; Event; Exhibits; Fatty acid glycerol esters; Goals; In Vitro; Individual; Inflammation; Inflammatory; LOX gene; Laboratories; Life; Ligands; Lipids; Mediating; Molecular; Molecular Models; Myocardial Infarction; Outcome; Pathology; Patients; Peripheral Vascular Diseases; Pharmacotherapy; Physiological; Polymers; Research; Research Personnel; Research Proposals; Serum; Staging; Stroke; Structure; Tail; Testing; Therapeutic; Thrombosis; Vascular Diseases; Vertebral column; arm; atherogenesis; base; cost; design; diabetic; hydrophilicity; improved; in vivo; in vivo Model; inflammatory marker; inhibitor/antagonist; innovation; insight; macrophage; molecular modeling; monocyte; mortality; novel; novel strategies; oxidized low density lipoprotein; receptor; receptor binding; response; scavenger receptor; sugar; therapy design; trigger point; uptake

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.

描述（由申请人提供）：这项研究针对动脉粥样硬化，这是血管壁的慢性炎症性疾病，其构成了西方国家所有死亡人数的近50％，是糖尿病患者死亡率的主要原因。该建议利用了一种新型的治疗剂 - 两亲性聚合物的合理分子设计方法，它们是动脉粥样硬化和抗炎疗法。最具创新性的成分是，分子设计的聚合物可能在动脉粥样硬化的早期阶段通过多个寻宝者受体靶向和阻塞来抑制动脉粥样硬化。这种结合行为对于阻止氧化的LDL摄取并更有效地消除了动脉炎的级联反应，并阻止动脉粥样硬化的进展至关重要。关于增强聚合物结构的中心假设是，加强疏水特征与阴离子电荷和亲水性尾巴结合的组合将产生与巨噬细胞和内皮细胞上多个清道夫受体的最佳靶向聚合物，特定于SR-A，CD36和LOX36和Lox36和Lox36和Lox36和Lox36和Lox36和Lox-1 。为了检验这一假设，提出了三个具体目标。 AIM 1的重点是分子建模（对接和评分）和新型聚合物类别的设计，以增强与多种寻求者受体的结合。这项工作将产生新的聚合物结构，具有更刚性和更空间的主链，结合电荷和亲水性，增强了与寻宝受体的结合亲和力，尤其是在生理条件下。 AIM 2的重点是研究分子机制和聚合物与培养的巨噬细胞和内皮细胞的相互作用，以抑制在体外动脉炎。 AIM 3的重点是使用加速动脉粥样硬化动物模型的动物模型来评估与动脉粥样硬化病变的结合和动脉粥样硬化标记的消退程度的评估。至少，将获得有关多种寻宝受体阻断的新见解，以此来抵消动脉粥样硬化的进展。这项研究建议的潜在影响很高。总体结果可能是一种使用增强的聚合物作为多功能抑制剂来治疗冠状动脉疾病的新方法。 公共卫生相关性：该项目与针对动脉粥样硬化的生物学活性和功效的聚合物生物材料的设计有关，脂质（脂肪）填充的血管的逐渐阻塞导致心脏病发作和中风，这是美国成年人死亡率的主要原因将深入了解聚合物之间的结构功能关系与它们对胆固醇摄取的阻塞之间的障碍；对抑制炎症的影响；以及改善可生物降解的聚合物材料作为治疗血管和炎症性疾病的治疗剂的鉴定。