Basic research on the diagnosis and therapy for abnormal brain aging caused by oxidative stress.

作为衰老相关模型小鼠P8倾向(SAMP8)脑内氧化应激增加的标志，用聚合酶链式反应(PCR)检测线粒体DNA缺失。此外，利用从SAMP8脑中分离的线粒体组分，确定了线粒体电子传递链上的负责部位。在SAMP8脑中，线粒体DNA缺失与耐药倾向(SAMR1)脑相比显著增加，即使在症状前的年轻年龄也是如此。在SAMP8脑中，线粒体呼吸过度活跃，呼吸控制率低于SAMR1。因此，可以说，在与年龄相关的功能障碍发生之前，线粒体电子传递链中就存在着一种低效的过度活跃状态。利用SAMP8和SAMR1，利用正电子发射放射性药物铜-ATSM阐明了脑内氧化应激诊断的可能性。在SAMP8脑中，一种新的缺氧标志物铜-ATSM比SAMR1具有更高的保留率，它可以通过正电子发射断层扫描(PET)检测电子传递失败。在这些发现的基础上，在我校伦理委员会的指导下开始了临床前研究。在正常志愿者中，除代谢排泄器官外，铜-ATSM在正常组织中没有明显蓄积，也没有明显的副作用。然后，作为第一个临床试验，我们对缺血性心脏病和肿瘤患者进行了诊断，并可以获得不稳定心绞痛和肺肿瘤的清晰图像。除了这些发现之外，我们还发现了不同脑病患者之间铜-PTSM的脑积聚差异。心理水平和铜-ATSM积累之间的可能关系将是下一个研究重点。

As a marker of increased oxidative stressin the brain of Senescence Accerelated Model mice P8 prone (SAMP8), mitochnodrial DNA deletion was evaluatedusing polymerase chain reaction (PCR). In addition, responsible site in mitochondrial electron transport chain was identified using mitochondrial fraction isolated from SAMP8 brain. In SAMP8 brain, significant increase in mitochondrial DNA deletion was found when compared with resistant prone (SAMR1) brain, even in pre-symptomatic young age. In SAMP8 brain, hyper activity of mitohcondrial respiration with lower respiration control ration than SAMR1. Thus, it can be said that an inefficient hyperactive state exists in the mitochondrial electron transport chain before the age-associated dysfunction develops.Using SAMP8 and SAMR1, the possibility of oxidative stress diagnosis in the brain was clarified using positron emitting radiopharmaceutical, Cu-ATSM.In SAMP8 brain, a novel hypoxia marker Cu-ATSM, which can detect the failure of electron transport using positron emission tomography (PET), highly retained than in SAMR1.Base on these finding, pre-clinical studies were started under the guide line of the Ethical Committee of our university. In normal volunteers, Cu-ATSM showed no significant accumulation in normal tissues, except for metabolic excretion organs, as well as no apparent side-effect. Then, as a first clinical trial, ischemic heart disease and tumor patients were diagnosed and clear image of unstable angina and lung tumor could be obtained.Independent from these findings, we found the interpatient differences in the brain accumulation of Cu-PTSM, a derivative of Cu-ATSM in various brain diseases. Possible relationship between mental levels and Cu-ATSM accumulation will be a next focus of the study.