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

氧化应激引起的脑异常衰老的诊断和治疗的基础研究。

基本信息

批准号：
09670930
负责人：
FUJIBAYASHI Yasuhisa
金额：
$ 1.86万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670930/
关键词：
senescense Mitochondria memory deterioration oxidative stress positron CT Cu-ATSM DNA deletion Cu-62 虚血性疾患ラジカル PCR

项目摘要

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.

作为衰老加速模型小鼠P8易感性（SAMP8）脑氧化应激增加的标志，采用聚合酶链反应（PCR）评估线粒体DNA缺失。此外，利用从SAMP8脑中分离的线粒体片段，确定了线粒体电子传递链的负责位点。在SAMP8大脑中，与耐药倾向（SAMR1）大脑相比，线粒体DNA缺失显著增加，即使在症状前的年轻人中也是如此。在SAMP8脑内，线粒体呼吸活动高，呼吸控制比SAMR1低。因此，可以说，在年龄相关功能障碍发生之前，线粒体电子传递链存在低效的过度活跃状态。利用SAMP8和SAMR1，利用正电子放射药物Cu-ATSM明确了脑内氧化应激诊断的可能性。在SAMP8大脑中，一种新的缺氧标志物Cu-ATSM，可以通过正电子发射断层扫描（PET）检测电子传递的失败，比SAMR1高保留。基于这些发现，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，Cu-ATSM在正常组织中无明显蓄积，也无明显副作用。然后，作为第一个临床试验，诊断缺血性心脏病和肿瘤患者，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Cu-PTSM （Cu-ATSM的衍生物）在不同脑部疾病中的脑累积在患者间的差异。心理水平与Cu-ATSM积累之间的可能关系将是下一步研究的重点。