项目名称: 铜螯合剂由抑制SOD1的活性调控胞内氧化还原信号转导
项目编号: No.21271079
项目类型: 面上项目
立项/批准年度: 2013
项目学科: 数理科学和化学
项目作者: 刘长林
作者单位: 华中师范大学
项目金额: 80万元
中文摘要: 铜锌超氧化物歧化酶(SOD1)催化超氧阴离子歧化为过氧化氢,维持胞内超氧和过氧化氢的内稳态浓度。NADPH氧化酶作为超氧的主要源之一,受细胞因子与其膜表面受体结合的刺激而活化将产生高浓度超氧,SOD1则导致胞内过氧化氢浓度显著上升。高浓度过氧化氢由可逆氧化活性部位的半胱氨酸残基使信号蛋白失活,激活胞内异常的氧化还原信号转导网络,或使正常的氧还信号网络失调。这既能导致细胞过度增殖,新血管生成,引起癌变;又能引起严重的炎症,损伤运动神经元,导致脊髓侧索硬化症(ALS)。因此,SOD1成了设计抗癌和抗ALS药物的重要靶标。合理组合beta折叠蛋白识别试剂和灵敏的胞内铜成像试剂,设计特异的螯合剂由去除SOD1中的铜使其失活,改变胞内超氧和过氧化氢的相对水平,调控氧还信号途径,由此选择性地导致细胞凋亡或死亡。这有助于设计由合理调控氧还信号网络,抑制细胞过度增殖和血管生成、减轻运动神经元损伤的药物。
中文关键词: SOD1;ROS;信号转导;金属螯合剂;抑制
英文摘要: Cu/Zn superoxide dismutase (SOD1) maintains the homeostasis of superoxide anion and peroxide hydrogen by catalyzing the dismutation of superoxide to peroxide hydrogen. NADPH oxidase (Nox) acts as one of the main superoxide sources. Upon the stimulation by the binding of cytokines to their receptors on membrane, Nox is activated, leading to the formation of superoxide at a high level.Thereby, SOD1 results in a significant increase in the concentration of peroxide hydrogen. Peroxide hydrogen at the high levels can inactivated signaling proteins by reversibly oxidazing the cysteine residues in their active sites, resulting in activation of the aberrant redox signaling network or dysregulation of the redox signaling network. This can cause not only the cellular responses such as hypertrophy, proliferation, and migration, but also angiogensis, leading to tumorigensis. Moreover, the aberrant redox signaling may cause inflammation and damage motor neurons, resulting in amyotrophic lateral sclerosis (ALS). Therfore, SOD1 has become a target for designing anticancer and anti-ALS drugs. Thioflavin T (ThT) is a fluorescent reagent sensetive to beta-sheet proteins and their aggregates, and the Cu bio-probes have a strong affinity for the intracellular Cu. Through rational combination of the recognition property of ThT for b
英文关键词: SOD1;ROS;signaling;chelator;inhibition