EFFECTS OF SHORT-AND LONG-TERM FLEX-HET THERAPY ON MITOCHONDRIAL ELECTRON

短期和长期 Flex-HET 疗法对线粒体电子的影响

• 批准号: 8167537
• 负责人: KELLY J WILLIAM
• 金额: $ 6.6万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167537
• 关键词: Animals; Apoptosis; Autopsy; Cell Death; Cells; Colon Carcinoma; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytochromes; Drug Delivery Systems; Electron Transport; Electrons; Freezing; Funding; Generations; Glutathione; Grant; Heart; Hepatocyte; Injury; Institution; Lead; Liver; Measures; Membrane; Mitochondria; Pharmaceutical Preparations; Publishing; Research; Research Personnel; Resources; SHetA2; Source; Submitochondrial Particles; Succinate Dehydrogenase; Succinate dehydrogenase (ubiquinone); Tissues; Ubiquinone; United States National Institutes of Health; cancer chemoprevention; density; inhibitor/antagonist; oxidative damage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have recently published our observation of the rapid effects of the lead Flex-Het compound, SHetA2, on mitochondrial density, membrane integrity, Cytochrome C release and ROS generation, all indicative of the intrinsic apoptosis pathway. More recently, we have observed that Flex-Hets are potent, uncompetitive inhibitors of mitochondrial electron transport chain complex I and also inhibitors of complex II. Since few inhibitors of both complex I and II are know at present, in the first part of this proposal we will further examine the effect of Flex-Het drugs on succinate dehydrogenase and full ubiquinone dependent succinate:ubiquinone oxidoreductase activity. However mitochondria targeting drugs may be a two-edged sword, ROS themselves are highly toxic to cells and mitochondria can gradually accumUlate oxidative damage leading to mitochondrial collapse and cell death. In the second part of this proposal we propose to assess the possibility of mitochondrial injury in heart and liver cells following long-term Flex-Het treatment. Markers of impaired mitochondrial function such as decreased cellular ATP, decreased mitochondrial glutathione and decreased complex I activity will be measured in both cells, mitochondria and submitochondrial particles isolated from snap-frozen heart and liver tissue obtained from animals sacrificed following necropsy in an ongoing long-term colon cancer chemoprevention project evaluating ShetA2.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们最近发表了我们对主要 Flex-Het 化合物 SHetA2 对线粒体密度、膜完整性、细胞色素 C 释放和 ROS 生成的快速影响的观察，所有这些都表明了内在的细胞凋亡途径。最近，我们观察到 Flex-Hets 是线粒体电子传递链复合物 I 的有效、非竞争性抑制剂，也是复合物 II 的抑制剂。由于目前对复合物 I 和 II 的抑制剂知之甚少，因此在本提案的第一部分中，我们将进一步研究 Flex-Het 药物对琥珀酸脱氢酶和完全泛醌依赖性琥珀酸：泛醌氧化还原酶活性的影响。然而线粒体靶向药物可能是一把双刃剑，ROS本身对细胞具有剧毒，线粒体会逐渐积累氧化损伤，导致线粒体崩溃和细胞死亡。在该提案的第二部分中，我们建议评估长期 Flex-Het 治疗后心脏和肝细胞线粒体损伤的可能性。线粒体功能受损的标志物，如细胞 ATP 减少、线粒体谷胱甘肽减少和复合物 I 活性降低，将在细胞、线粒体和亚软骨颗粒中进行测量，这些颗粒是从快速冷冻的心脏和肝脏组织中分离出来的，这些组织是在一项评估 ShetA2 的长期结肠癌化学预防项目中进行的评估 ShetA2 的长期结肠癌化学预防项目中从尸检后处死的动物获得的。