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: 10461066
• 负责人: Joseph L. Witztum
• 金额: $ 36.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461066
• 关键词: Acetaldehyde; Adipocytes; Antibodies; Antibody titer measurement; Arteries; Atherosclerosis; Biological Markers; Blood Circulation; CCL4 gene; Cardiovascular system; Cells; Cholesterol; Chronic; Collagen Gene; Complex; Consumption; Coronary Arteriosclerosis; Data; Development; Diet; Disease; Disease Progression; Epitopes; Event; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Free Radical Formation; Fructose; Gene Expression; 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; Population; Predictive Value; Proteins; Publishing; Reaction; Risk; Risk Factors; Role; Testing; Therapeutic; Therapeutic Studies; Tissues; Transgenic Mice; Vaccines; adduct; atherogenesis; base; biomarker performance; burden of illness; cohort; diabetic; improved; in vivo; innovation; insight; liver inflammation; macrophage; mouse model; neoantigens; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; oxidized low density lipoprotein; prevent; risk sharing; translational applications; translational study; translational therapeutics

PROJECT SUMMARY Project 3. Pivotal Role of Oxidation-specific Epitopes in CVD and NASH 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 NAFLD are at increased risk for CVD, and share common risk factors. However, NAFLD confers additional risk for CVD above that due to known shared risk factors. This Project 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 using newly generated 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.

项目摘要 项目3。氧化特异性表位在CVD和NASH中的关键作用 脂质过氧化是动脉粥样硬化和NASH中的中心事件，导致形成氧化特异性表位 （OSE），例如氧化磷脂（OXPL），丙二醛（MDA）和称为MAA的复杂MDA加合物， 我们称其为“氧化特异性 - 杰出人物”（OSE）。它们是促炎的，并促进了慢性 炎。因为OSE主要是非酶脂质过氧化的产物，所以特定的机制 到目前为止，中和它们在疾病状态（例如动脉粥样硬化状态）中的实际作用是无法获得的 纳什未知。项目3的重点是了解OSE在动脉粥样硬化和 纳什和它们为这些疾病做出贡献的常见（或独特的）机制。这是可行的 基于我们最新的转基因小鼠的发展，该小鼠构成表达单链抗体 靶OXPL- E06-SCFV小鼠 - 或靶向MDA/MAA-IK17-SCFV小鼠。在最近出版和新的 初步数据我们证明，靶向食用NASH饮食的小鼠的OXPL都会下降 动脉粥样硬化和纳什。初步研究表明，靶向MDA/MAA也可以减少 纳什模型中动脉粥样硬化和肝脏注射的进展。 NAFLD患者的CVD风险增加，并具有共同的危险因素。但是，NAFLD承认 由于已知的共享风险因素，CVD的额外风险高于该风险。该项目将检验以下假设 OSE是先前未知的共同危险因素。独特的是，这个项目将仅关注 OSE在动脉粥样硬化和NASH的发病机理中的作用，并通过 促进这些疾病。具体目标1将使用E06-SCFV转基因小鼠研究 小鼠模型中的动脉粥样硬化和肝脂肪变性/NASH/纤维化中的OXPL，并确定是否针对OXPL 可以轻松地减少动脉和肝脏的疾病燃烧。我们将使用E06-SCFV小鼠 研究OXPL中和影响动脉粥样硬化和肝病的特定机制。 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 在与目标1的并行研究中的小鼠模型。特定目标3是OSE在CVD中作用的翻译研究 和NAFLD/NASH，并将寻求确定针对OXPL和/或MDA/MAA是否可以防止 疾病的进展，但会导致现有疾病的消退。这将使用新的 产生的转基因小鼠有条件地表达靶向OSE的抗体，以便增强的滴度可以 在建立疾病后可以实现。这将使研究能够确定靶向OSE是否可以是治疗 并减少伯恩疾病。这些研究应提供对新的常见风险因素的理解 连接纳什和动脉粥样硬化。因为抗体介导的中和OSE的方法可能针对 纳什（Nash）和动脉粥样硬化的作用都很简单，这些研究可能会导致创新的翻译应用。