Nanoscale Receptor Blockers for Inhibition of Atherosclerosis

描述（由申请人提供）：由氧化脂质不受控制的积聚引起的血管病变导致动脉粥样硬化，这是一种严重的心血管疾病，是美国成年人死亡的最常见原因（每年超过100万患者）。现有的治疗策略很少涉及动脉粥样硬化（血管壁氧化脂质积聚）和相关炎症的局部管理。本研究的总体目标是合理设计和表征纳米级生物材料，作为一种新的细胞靶向材料平台，用于研究降低动脉粥样硬化发作和减少伴随炎症的策略。NIH R21研究包括三个特定目标，研究纳米组装两亲性聚合物（nap）在生理条件下最大限度地抑制人巨噬细胞氧化LDL摄取，并显示出特异性靶向炎症内皮的潜力。Aim 1的工作将包括研究纳米组装两亲性聚合物（NAP）的组成和结构的创新设计，以促进NAP与人THP-1巨噬细胞上的SRA-1和CD36清扫剂受体结合，从而抑制氧化低密度脂蛋白（oxLDL）的摄取。新配置的NAP将测试改善脂质摄取抑制存在的血清。Aim 2的研究将研究NAP-scavenger receptor （SR）相互作用对调节巨噬细胞动脉粥样硬化的下游细胞内和细胞分泌中间体的影响，包括细胞因子分泌；胆固醇酯积累；基质金属蛋白酶分泌；以及促动脉粥样硬化信号通路相关基因的表达分析。目的3是设计和评估生物功能化nap在体外与活化内皮细胞培养物结合和转运的潜力，从而创建一个简化的体外模型，以拯救参与血管内膜动脉粥样硬化的巨噬细胞。

DESCRIPTION (provided by applicant): Pathologies in blood vessels arising from the uncontrolled build-up of oxidized lipids contribute to atherosclerosis, a severe cardiovascular disease, which underlies the most common cause of adult death in the U.S. (exceeding one million patients yearly). Few existing therapeutic strategies address the local management of atherogenesis (build-up of oxidized lipids in the blood vessel walls) and related inflammation. The overall goals of this study are to rationally design and characterize nanoscale biomaterials as a novel cell-targeted materials platform for investigating strategies to de-escalate the onset of atherogenesis and reduce accompanying inflammation. The proposed NIH R21 study involves three specific objectives to investigate nanoassembled amphiphilic polymers (NAPs) to maximally inhibit oxidized LDL uptake in human macrophages under physiologic conditions and exhibit potential for specific targeting to inflamed endothelia. Efforts in Aim 1 will involve investigation of innovative designs of nano-assembled amphiphilic polymers (NAP) composition and architecture to promote NAP binding to both SRA-1 and CD36 scavenger receptors on human THP-1 macrophages and thus inhibit uptake of oxidized low-density lipoproteins (oxLDL). New configurations of NAP will tested for improved lipid uptake inhibition in the presence of serum. Studies in Aim 2 will investigate the effect of NAP-scavenger receptor (SR) interactions on the downstream intracellular and cell-secreted intermediates regulating atherogenesis in macrophages, including cytokine secretion; cholesterol ester accumulation; matrix metalloproteinase secretion; and expression analysis of genes involved in pro-atherogenic signaling pathways. Aim 3 is concerned with design and evaluation of the potential of biofunctionalized NAPs to bind to and transport across activated endothelial cell cultures in vitro, thereby creating a simplified in vitro model of the rescue of macrophage cells involved in atherogenesis within the vascular intima. PUBLIC HEALTH RELEVANCE: The excessive uptake of modified forms of LDL in immune blood cells macrophages is one of the hallmarks of fat build-up and vascular disease within blood vessel walls, which can lead to blockage of blood flow, and cause heart disease or stroke. This study will investigate the design of nanoscale assembled polymers with specific architectures, charge displays, and chemistry so as to reduce the uptake of the most damaging forms of lipoproteins within macrophages. The goals of the study are to identify the most effective "nanolipoblocker" configurations that may prevent atherogenesis by targeting activated blood vessel cells and blocking foam cell formation.