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: 10262920
• 负责人: Joseph L. Witztum
• 金额: $ 36.84万
• 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/10262920
• 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; Gap Junctions; Gene Expression; 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; 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; macrophage; mouse model; neoantigens; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; oxidized low density lipoprotein; prevent; risk sharing; translational study

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.

项目总结