Pivotal Role of Oxidation-specific Epitopes in CVD and NASH

氧化特异性表位在 CVD 和 NASH 中的关键作用

• 批准号: 9803625
• 负责人: Joseph L. Witztum
• 金额: $ 55.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-07 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803625
• 关键词: Acetaldehyde; Antibodies; Antibody titer measurement; Arteries; Atherosclerosis; Biological Assay; Biological Markers; Blood Circulation; CCL4 gene; Cells; Chronic; Collagen Gene; Complex; Consumption; Data; Development; Diet; Disease; Disease Progression; Epitopes; Event; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Free Radical Formation; Fructose; Gene Expression; Generations; Hepatic; Hepatocyte; Human; Immune Targeting; Inflammation; Inflammatory; Lead; Lipid Peroxidation; Liver; Liver Fibrosis; Liver diseases; Low Density Lipoprotein oxidation; Malondialdehyde; Mediating; Mitochondria; Modeling; Molecular; Mus; Nature; Oxides; Pathogenesis; Patients; Pattern; Phospholipids; Plasma; Population; Proteins; Publishing; Reaction; Research; Risk; Risk Factors; Role; Testing; Therapeutic; Therapeutic Studies; Tissues; Transgenic Mice; Vaccines; adduct; atherogenesis; base; burden of illness; cohort; diabetic; feeding; improved; in vivo; innovation; insight; macrophage; mouse model; neoantigens; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; oxidized low density lipoprotein; prevent; risk sharing; translational approach; translational study

Summary Lipid peroxidation, a central event in atherogenesis and NASH, results in formation of oxidation-specific epitopes (OSE) such as oxidized phospholipids (OxPL), malondialdehyde (MDA) and complex MDA adducts termed MAA, which we termed “oxidation-specific-epitopes” (OSE). They are proinflammatory and promote chronic inflammation. Because OSE are mostly products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them were unavailable until now and their actual roles in vivo in disease states such as atherosclerosis and NASH are unknown. Project 3 is focused on understanding the role of OSE in both atherosclerosis and NASH and the common (or unique) mechanisms by which they contribute to these diseases. This is now feasible based on our recent development of transgenic mice that constitutively express single chain antibodies that target OxPL--the E06-scFv mice—or target MDA/MAA—the IK17-scFv mice. In recently published and new preliminary data we demonstrate that targeting OxPL in mice consuming NASH producing diets decreases both atherosclerosis and NASH. Preliminary studies demonstrate that targeting of MDA/MAA can also reduce the progression of atherosclerosis and hepatic inflammation in a NASH model. Patients with NASH are at increased risk for CVD, and share common risk factors. However, NASH confers additional risk for CVD above that due to known shared risk factors. This Application will test the hypothesis that OSE are a previously unrecognized common risk factor. Uniquely, this project will simultaneously focus on the role of OSE in the pathogenesis of atherosclerosis and NASH and define common (or distinct) mechanisms by which OSE promote these diseases. Specific Aim 1 will use the E06-scFv transgenic mice to study the Role of OxPL in Atherosclerosis and Hepatic Steatosis/NASH/Fibrosis in mouse models and determine if targeting OxPL can simultaneously reduce disease burden in both the artery and liver. We will use the E06-scFv mice to investigate the specific mechanisms by which neutralization of OxPL impacts atherogenesis and liver disease. Specific Aim 2 will study the Role of MDA/MAA in Atherosclerosis and Hepatic Steatosis/NASH/ Fibrosis in mouse models in parallel studies to Aim 1. Specific Aim 3 are Translational Studies of the Role of OSE in CVD and NAFLD/NASH and will seek to determine if targeting OxPL and/or MDA/MAA can not only prevent progression of disease but cause regression of existing disease. This will be accomplished by generating transgenic mice that conditionally express the antibodies targeting OSE so that enhanced titers can be achieved after disease is established. This will allow studies to determine if targeting OSE can be therapeutic and reduce disease burden. These studies should provide an understanding of novel common risk factors connecting NASH and atherogenesis. Because an antibody-mediated approach to neutralize OSE could target both NASH and atherogenesis simultaneously, these studies may lead to innovative translational applications.

总结 脂质过氧化是动脉粥样硬化和NASH的中心事件，导致氧化特异性表位的形成 (OSE)例如氧化磷脂（OxPL）、丙二醛（MDA）和称为MAA的复合MDA加合物， 我们称之为"氧化特异性表位"（OSE）。它们是促炎性的， 炎症由于OSE主要是非酶脂质过氧化的产物， 直到现在还不能中和它们，它们在诸如动脉粥样硬化的疾病状态中的体内实际作用 和NASH是未知的。项目3的重点是了解OSE在动脉粥样硬化和 NASH及其导致这些疾病的共同（或独特）机制。这现在是可行的 基于我们最近开发的组成型表达单链抗体的转基因小鼠， 靶向OxPL-E06-scFv小鼠-或靶向MDA/MAA-IK17-scFv小鼠。在最近出版的和新的 我们的初步数据表明，在消耗NASH产生饮食的小鼠中靶向OxPL， 动脉粥样硬化和NASH。初步研究表明，靶向MDA/MAA也可以减少 NASH模型中动脉粥样硬化和肝脏炎症的进展。 NASH患者的CVD风险增加，并且具有共同的风险因素。然而，NASH赋予 CVD的额外风险高于已知的共同风险因素。本申请将检验以下假设： OSE是以前未被认识到的常见风险因素。独特的是，该项目将同时关注 OSE在动脉粥样硬化和NASH发病机制中的作用，并通过以下方式定义共同（或不同）机制： 哪些OSE促进了这些疾病。具体目标1将使用E06-scFv转基因小鼠来研究E06-scFv的作用。 OxPL在小鼠模型中的动脉粥样硬化和肝脂肪变性/NASH/纤维化中的作用，并确定是否靶向OxPL 可以同时减轻动脉和肝脏的疾病负担。我们将使用E06-scFv小鼠， 研究OxPL的中和作用影响动脉粥样硬化形成和肝脏疾病的具体机制。 具体目标2将研究MDA/MAA在动脉粥样硬化和肝脂肪变性/NASH/纤维化中的作用， 小鼠模型与目标1平行研究。具体目标3是OSE在CVD中作用的转化研究 和NAFLD/NASH，并将寻求确定靶向OxPL和/或MDA/MAA是否不仅可以预防 疾病进展，但导致现有疾病的消退。这将通过生成 条件性表达靶向OSE的抗体的转基因小鼠，以便实现增强的滴度 疾病建立后。这将使研究能够确定靶向OSE是否具有治疗作用， 疾病负担。这些研究应该提供对NASH相关的新的常见风险因素的理解 和动脉粥样硬化。因为中和OSE的抗体介导的方法可以靶向NASH和 同时，这些研究可能导致创新的转化应用。