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GAPDH, DNA Repair and Atherosclerosis

GAPDH、DNA 修复和动脉粥样硬化

基本信息

批准号：
10421067
负责人：
Sergiy Sukhanov
金额：
$ 38万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421067
关键词：
Acute Apoptosis Apoptotic Arterial Fatty Streak Arteries Atherosclerosis Binding Blood Vessels Cardiovascular Diseases Carotid Artery Plaques Cells Collagen Complementary DNA Coronary heart disease DNA DNA Damage DNA Repair DNA Repair Enzymes DNA Repair Pathway Data Dependovirus Development Diagnostic Disease Down-Regulation Enzymes Event Genomic Instability Glyceraldehyde-3-Phosphate Dehydrogenases Glycolysis Goals Heart Homeostasis Human Lesion Link Lipids Mediating Molecular Morbidity - disease rate Mus Necrosis Neurodegenerative Disorders Nuclear Oxidants Oxidation-Reduction Oxidative Stress Oxides Peptides Pharmaceutical Preparations Play Prevention Role Rupture Signal Transduction Smooth Muscle Myocytes Specimen Testing Therapeutic Thick Thinness Vascular Smooth Muscle atherogenesis atheroprotective base endonuclease gain of function healthy lifestyle improved in vivo in vivo evaluation innovation loss of function mortality mouse model new therapeutic target novel overexpression oxidized low density lipoprotein prevent repaired sensor vector

项目摘要

Project Summary/Abstract Accumulated DNA damage is recognized as a causal factor in the initiation and progression of atherosclerosis. Genomic instability in the vascular smooth muscle cells (SMC) leads to cell apoptosis and contributes to atherosclerotic plaque vulnerability. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is the major cellular sensor ultimately responsible for maintaining of cellular homeostasis, however its specific role in atherogenesis is completely unknown. It has been shown that a key pro-atherogenic lipid OxLDL downregulated GAPDH in human aortic SMC and that GAPDH expression was markedly decreased in the atherosclerotic plaque SMC and that low GAPDH level was associated with increased apoptosis. GAPDH reduced DNA damage and suppressed SMC apoptosis via a novel molecular mechanism involving nuclear GAPDH interaction with apurinic/apyrimidinic endonuclease 1 (Ape1), the major oxidized DNA repair enzyme. SMC-specific GAPDH overexpression decreased DNA damage, reduced plaque SMC apoptosis and decreased atherosclerotic burden. Importantly, atherosclerotic plaques in GAPDH-overexpressing mice had elevated SMC levels, increased collagen, reduced necrotic cores and thicker SMC-rich fibrous caps suggesting enhanced plaque stability. The major focus of the current proposal is to study the mechanism mediating GAPDH-induced anti-atherosclerotic and plaque stabilizing effect and to determine whether GAPDH mimicking peptide (GMP) reduces atherosclerotic burden and improve plaque stability in atherosclerotic mice. The main hypothesis is that GAPDH reduces atherosclerotic burden and enhances features of plaque stability via stimulation of Ape1-dependent DNA repair and suppression of SMC apoptosis. This will test the hypothesis in following Specific Aims: Specific Aim 1: To demonstrate that SMC-specific GAPDH regulates DNA repair, apoptosis, atherosclerotic burden and features of plaque stability and identify mechanism. Specific Aim 2: To determine whether GAPDH-mimicking peptide (GMP) will activate Ape1, stimulate DNA repair, suppress cell apoptosis and reduce atherosclerosis. Proposal will use adeno-associated viruses (AAVs) to perform SMC-targeted GMP cDNA transfer in atherosclerotic mice. AAV-based vectors are approved to use in humans, therefore the long-term goal is to use the AAV-GMP vector as an innovative pro-DNA repair and anti-apoptotic therapy to treat unstable atherosclerosis. Studying of anti-atherosclerotic effects of GAPDH and demonstration that GMP induces plaque-stabilizing effect will lead to the development of novel targeted therapies to treat atherosclerosis and prevent acute vascular events.

项目概要/摘要累积的DNA损伤被认为是动脉粥样硬化发生和进展的致病因素。血管平滑肌细胞 (SMC) 的基因组不稳定性会导致细胞凋亡并导致动脉粥样硬化斑块脆弱性。 3-磷酸甘油醛脱氢酶（GAPDH）是主要的酶细胞传感器最终负责维持细胞稳态，但其具体作用动脉粥样硬化形成是完全未知的。研究表明，一种关键的促动脉粥样硬化脂质 OxLDL 下调人主动脉 SMC 中的 GAPDH 表达，并且在动脉粥样硬化斑块 SMC 和低 GAPDH 水平与细胞凋亡增加相关。甘草酸脱氢酶通过涉及核的新型分子机制减少 DNA 损伤并抑制 SMC 凋亡 GAPDH 与无嘌呤/无嘧啶核酸内切酶 1 (Ape1)（主要的氧化 DNA 修复酶）相互作用。 SMC 特异性 GAPDH 过表达可减少 DNA 损伤、减少斑块 SMC 细胞凋亡和减少动脉粥样硬化负担。重要的是，GAPDH 过表达小鼠的动脉粥样硬化斑块 SMC 水平升高、胶原蛋白增加、坏死核心减少和富含 SMC 的纤维帽变厚，表明增强斑块稳定性。当前提案的主要重点是研究中介机制 GAPDH 诱导的抗动脉粥样硬化和斑块稳定作用并确定 GAPDH 是否模仿肽（GMP）可减轻动脉粥样硬化小鼠的动脉粥样硬化负担并改善斑块稳定性。主要假设 GAPDH 通过减少动脉粥样硬化负担并增强斑块稳定性刺激 Ape1 依赖性 DNA 修复并抑制 SMC 凋亡。这将检验假设以下具体目标：具体目标 1：证明 SMC 特异性 GAPDH 调节 DNA 修复、细胞凋亡、动脉粥样硬化负荷和斑块稳定性的特征并确定机制。具体目标 2：确定 GAPDH 模拟肽 (GMP) 是否会激活 Ape1、刺激 DNA修复，抑制细胞凋亡，减轻动脉粥样硬化。提案将使用腺相关病毒 (AAV) 在 SMC 中进行靶向 GMP cDNA 转移动脉粥样硬化小鼠。基于 AAV 的载体被批准用于人类，因此长期目标是使用 AAV-GMP 载体作为创新的 DNA 修复和抗凋亡疗法来治疗不稳定动脉粥样硬化。 GAPDH抗动脉粥样硬化作用的研究及GMP诱导的论证斑块稳定作用将导致开发新的靶向疗法来治疗动脉粥样硬化和预防急性血管事件。