Nanoscale Receptor Blockers for Inhibition of Atherosclerosis

描述(申请人提供)：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100万名患者)。现有的治疗策略很少涉及动脉粥样硬化形成(氧化脂质在血管壁中积聚)和相关炎症的局部管理。这项研究的总体目标是合理地设计和表征纳米生物材料作为一种新型的细胞靶向材料平台，以研究降低动脉粥样硬化形成和减少伴随的炎症的策略。拟议的NIH R21研究涉及三个具体目标，即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对氧化低密度脂蛋白的摄取，并显示出针对炎症内皮细胞的特异性靶向的潜力。目标1的工作将包括研究创新设计的纳米组装两亲性聚合物(NAP)的组成和结构，以促进NAP与人THP-1巨噬细胞上的SRA-1和CD36清道夫受体结合，从而抑制氧化低密度脂蛋白(OxLDL)的摄取。新构型的NAP将在有血清存在的情况下测试改善的脂质摄取抑制。AIM 2的研究将探讨NAP-清道夫受体(SR)相互作用对调节巨噬细胞内动脉粥样硬化形成的下游细胞内和细胞分泌中间产物的影响，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参与促动脉粥样硬化信号通路的基因的表达分析。目的3设计和评价生物功能化的NAP在体外与激活的内皮细胞结合和转运的潜力，从而建立一个简化的体外拯救参与血管内膜动脉粥样硬化形成的巨噬细胞的模型。 与公共卫生相关：免疫血细胞巨噬细胞过度摄取修饰形式的低密度脂蛋白是脂肪积聚和血管壁血管疾病的特征之一，这可能导致血液流动堵塞，并导致心脏病或中风。这项研究将研究具有特定结构、电荷显示和化学的纳米级组装聚合物的设计，以减少巨噬细胞对最具破坏性的脂蛋白的摄取。这项研究的目标是确定最有效的纳米阻滞剂配置，通过靶向激活的血管细胞和阻止泡沫细胞的形成来防止动脉粥样硬化的形成。

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.