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

动脉壁炎症的体外和体内方法

基本信息

批准号：
7647662
负责人：
Alan M Fogelman
金额：
$ 40.02万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647662
关键词：
Aftercare Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoprotein E Apolipoproteins Apolipoproteins A Arteries Atherosclerosis Binding Binding Proteins Cells Chronic Coronary heart disease D-4F peptide Development Dose Enzymes Excision Foundations Grant Haptoglobins Heme Hemoglobin Hemolysis Hemopexin High Density Lipoprotein Cholesterol High Density Lipoproteins Human Hyperlipidemia In Vitro Inflammation Inflammatory Intestines Iron Knockout Mice Knowledge Lesion Lipids Lipoproteins Measures Metabolism Mus Myocardial Infarction Nuclear Orphan Receptor Oral Oral Administration Oxidants Pathway interactions Patients Pennsylvania Peptides Peroxidases Pharmacologic Substance Phase Plasma Principal Investigator Production Property Proteins Publishing Reporting Role Serum Stroke Testing Therapeutic Toxic effect Universities Whole Blood Work base cytokine design drug development heme oxygenase-1 human HNF4A protein improved in vivo insight macrophage mimetics mouse model novel novel diagnostics oxidized lipid research clinical testing transcription factor treatment strategy vascular inflammation

项目摘要

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.

项目 2 将重点关注载脂蛋白模拟肽。因为这些化合物似乎具有广义的抗炎特性，该信息可能对限速提供大量信息炎症以及动脉粥样硬化形成的步骤。目标 1 是确定 apoA-l 的机制模拟肽在血浆浓度比其低几个数量级时具有抗炎作用 apoA-l。在患有 CHD 和促炎 HDL 的患者中，单次口服剂量的 D-4F 可产生血浆水平~4纳摩尔并显着提高HDL的抗炎特性。怎么可能一个当 apoA-1 的浓度在患者血浆为-35微摩尔？我们推测 apoA-l 的抗炎特性模拟肽源自其结合促炎性氧化脂质的能力，其 KD 为多个数量级幅度小于人类 apoA-l。我们假设显着的抗炎特性 apoA-l 模拟肽还与其抑制促炎细胞因子产生的能力有关，但不抑制抗氧化酶的诱导，例如血红素加氧酶-1 (HO-1)。目标2是调查载脂蛋白模拟肽降低血红素结合和含血红素含量的机制 HDL 中的蛋白质并减少血管炎症。 apoA-1模拟肽的施用显着减少了这些 HDL 相关蛋白。我们假设这些蛋白质与 HDL 导致铁通过刺激促炎物质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 apoA-l 模拟物肽减少 HDL 中含铁蛋白的结合分子，从而改变这些含铁蛋白蛋白质远离 HDL，并允许它们通过不刺激促炎的途径进入巨噬细胞细胞因子，但确实诱导 HO-1。目标 3 是确定机制氯硝柳胺使由所有 L-氨基酸合成的载脂蛋白模拟肽具有生物活性当口服给药时。目标 4 是确定载脂蛋白模拟肽的作用机制促进肠道内apoA-l的合成。