权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Studies on molecular mechanisms of anti-apoptotic signals in glial cells

胶质细胞抗凋亡信号的分子机制研究

基本信息

批准号：
14370782
负责人：
MATSUDA Toshio
金额：
$ 8.9万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14370782/
关键词：
astrocyte microglia apoptosis cell death mitochondria nitric oxide (NO)SEA0400 T-817 神経細胞 Na^+Ca^<2+>交換系過酸化水素 cyclic GMP Ca^<2+>permeability transition pore (PTP)プロテインキナーゼ

项目摘要

The present study examined the molecular mechanisms of cell death in cultured neurons, astrocytes and microglia and the following results were obtained.First, we studied the mitochondrial permeability transition pore (mPTP) in rat brain and liver. (1)mPTP responded to reactive oxygen species (ROS) as well as Ca^<2+>. (2)Ca^<2+> induced ROS production in mitochondria. (3)The effect of ROS on mPTP was affected by cGMP and ATP. (4)The effects of ROS and Ca^<2+> on mPTP were accompanied by release of cytochrome c which triggers apoptosis. These results suggest that Ca^<2+>-induced opening of mPTP is mediated by production of ROS. Second, we studied the roles of the Na^+/Ca^<2+> exchanger (NCX) using the inhibitor SEA0400. We demonstrated the protective role of the inhibitor in models of cardiac dysfunction and brain edema and the physiological and pathological roles of NCX in various experimental conditions. Third, we studied the mechanisms of nitric oxide (NO)-induced cytotoxicity in cultured microglia, astrocytes and neurons. NO treatment resulted in cell death and the cytotoxicity was accompanied by mitochondrial dysfunction in cultured neurons, astrocytes and microglia. NO-induced cell toxicity in cultured microglia was attenuated by SEA0400 and edaravone. NO-induced cell toxicity in cultured neurons was attenuated by T-817. In microglia, endoplasmic reticulum stress-induced dysfunction of Ca^<2+> regulation plays a key role in NO-induced cell toxicity. The present results imply that NCX is involved in NO-related diseases.

本研究从分子水平探讨了体外培养的神经元、星形胶质细胞和小胶质细胞死亡的机制，并获得了以下结果：首先，我们研究了大鼠脑和肝线粒体通透性转换孔（mPTP）。（1）mPTP对活性氧（ROS）和Ca^<2+>均有反应。(2)Ca^<2+>诱导线粒体产生ROS。（3）ROS对mPTP的作用受cGMP和ATP的影响。（4）ROS和Ca^<2+>对mPTP的影响伴随着细胞色素c的释放而发生凋亡。这些结果表明，Ca^<2+>诱导的mPTP开放是由ROS的产生介导的。其次，我们使用抑制剂SEA 0400研究了Na^+/Ca^<2+>交换器（NCX）的作用。我们证明了抑制剂在心功能不全和脑水肿模型中的保护作用，以及NCX在各种实验条件下的生理和病理作用。第三，我们研究了一氧化氮（NO）诱导小胶质细胞、星形胶质细胞和神经元细胞毒性的机制。NO处理导致细胞死亡，细胞毒性伴随着线粒体功能障碍，在培养的神经元，星形胶质细胞和小胶质细胞。SEA 0400和依达拉奉可减弱NO诱导的小胶质细胞毒性。T-817可减轻NO诱导的神经细胞毒性。在小胶质细胞中，内质网应激诱导的Ca^<2+>调节功能障碍在NO诱导的细胞毒性中起关键作用。目前的结果表明，NCX参与了NO相关疾病。