An In-Vitro and In-Vivo Approach to Artery Wall Inflammation

项目2将重点研究载脂蛋白模拟多肽。因为这些化合物似乎具有 广义的抗炎特性，这一信息很可能是限速的高度信息量 参与炎症和动脉粥样硬化形成的步骤。目的1确定载脂蛋白A-L的作用机制(S) 模拟多肽在血浆浓度低于数量级时具有抗炎作用。 载脂蛋白A的L。在冠心病和促炎性高密度脂蛋白患者中，单剂量口服D-4F可产生血浆 ~4纳摩尔水平，并显著改善高密度脂蛋白的抗炎性能。怎么可能是一个 ~4纳摩尔的载脂蛋白A-L模拟肽的浓度在载脂蛋白A-L在 患者血浆为-35微摩尔？我们推测载脂蛋白A-L的抗炎作用 模拟多肽源于它们与致炎氧化脂质结合的能力，Kd为许多数量级 震级小于人类载脂蛋白A-L。我们推测其显著的抗炎作用 载脂蛋白A-L模拟肽还与其抑制促炎细胞因子产生的能力有关，而不是 抑制血红素加氧酶-1(HO-1)等抗氧化酶的诱导。目标2是调查 载脂蛋白模拟肽降低血红素结合量和含血量的机制(S) 高密度脂蛋白中的蛋白质和减少血管炎症。载脂蛋白A-L模拟肽的给药 显著减少了这些与高密度脂蛋白相关的蛋白质。我们假设这些蛋白质与 高密度脂蛋白使铁通过刺激促炎因子产生的途径进入巨噬细胞。 细胞因子而不刺激抗氧化酶，如HO-1。我们假设载脂蛋白A-L类似于 多肽减少了高密度脂蛋白中含铁蛋白质的结合分子，从而改变了这些含铁蛋白质。 蛋白质远离高密度脂蛋白，并允许它们通过不刺激促炎的途径进入巨噬细胞 但能诱导HO-1的细胞因子。目的3是为了确定。(S)通过 氯硝柳胺使所有L氨基酸合成的载脂蛋白模拟肽具有生物活性 当口服时。目的4确定载脂蛋白模拟肽的作用机制(S) 促进肠道内载脂蛋白A-L的合成。

Project 2 will focus on apolipoprotein mimetic peptides. Because these compounds appear to have generalized anti-inflammatory properties, this information is likely to be highly informative of rate-limiting steps in inflammation, as well as in atherogenesis. Aim 1 is to determine the mechanism(s) by which apoA-l mimetic peptides are anti-inflammatory at plasma concentrations that are orders of magnitude less than that of apoA-l. In patients with CHD and pro-inflammatory HDL, a single oral dose of D-4F produced plasma levels of ~4 nanomolar and significantly improved the anti-inflammatory properties of HDL. How could a concentration of ~4 nanomolar of an apoA-l mimetic peptide be effective when the concentration of apoA-l in the patient plasma was -35 micromolar? We hypothesize that the anti-inflammatory properties of apoA-l mimetic peptides derives from their ability to bind pro-inflammatory oxidized lipids with a KD many orders of magnitude less than human apoA-l. We hypothesize that the remarkable anti-inflammatory properties of apoA-l mimetic peptides also relate to their ability to inhibit pro-inflammatory cytokine production while not inhibiting the induction of anti-oxidant enzymes such as heme oxygenase-1 (HO-1). Aim 2 is to investigate the mechanism(s) by which apolipoprotein mimetic peptides reduce the content of heme-binding and hemecontaining proteins in HDL and reduce vascular inflammation. Administration of an apoA-l mimetic peptide dramatically reduced these HDL-associated proteins. We hypothesize that the binding of these proteins to HDL causes iron to enter macrophages via pathways that stimulate the production of pro-inflammatory cytokines without stimulating anti-oxidant enzymes such as HO-1. We hypothesize that apoA-l mimetic peptides reduce the binding molecules in HDL for iron containing proteins, thus shifting these iron containing proteins away from HDL and allowing them to enter macrophages by pathways that do not stimulate proinflammatory cytokines but which do induce HO-1. Aim 3 is to determine.the mechanism(s) by which niclosamide enables apolipoprotein mimetic peptides synthesized from all L-amino acids to be bioactive when administered orally. Aim 4 is to determine the mechanism(s) by which apolipoprotein mimetic peptides promote apoA-l synthesis in the intestine.