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，是美国成人死亡的最常见原因（每年超过一百万患者）。现有的治疗策略很少涉及动脉粥样硬化形成（血管壁中氧化脂质的积聚）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型的细胞靶向材料平台，用于研究降低动脉粥样硬化发生和减少伴随炎症的策略。拟议的NIH R21研究涉及三个具体目标，以研究纳米组装的两亲性聚合物（NAP）在生理条件下最大限度地抑制人巨噬细胞中的氧化LDL摄取，并表现出特异性靶向炎症内皮细胞的潜力。目标1的努力将涉及纳米组装的两亲性聚合物（NAP）组成和结构的创新设计的研究，以促进NAP与人THP-1巨噬细胞上的SRA-1和CD 36清道夫受体结合，从而抑制氧化低密度脂蛋白（oxLDL）的摄取。将测试NAP的新构型在血清存在下改善的脂质摄取抑制。目标2中的研究将研究NAP-清道夫受体（SR）相互作用对调节巨噬细胞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的基因的表达分析致动脉粥样硬化信号通路。目的3涉及设计和评估生物功能化的NAP在体外结合并转运穿过活化的内皮细胞培养物的潜力，从而创建拯救参与血管内膜内动脉粥样硬化形成的巨噬细胞的简化体外模型。 公共卫生相关性：免疫血细胞巨噬细胞中LDL修饰形式的过量摄取是血管壁内脂肪积聚和血管疾病的标志之一，这可能导致血流阻塞，并导致心脏病或中风。本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，以减少巨噬细胞内最具破坏性形式的脂蛋白的摄取。该研究的目的是确定最有效的“纳米脂质阻断剂”配置，可以通过靶向激活的血管细胞和阻断泡沫细胞形成来预防动脉粥样硬化。

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.