多重谷氨酸次型受體導致腦中風後神經元死亡之機制－多重谷氨酸次型受體導致腦中風後神經元死亡之機制(2/3)

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题名:	多重谷氨酸次型受體導致腦中風後神經元死亡之機制－多重谷氨酸次型受體導致腦中風後神經元死亡之機制(2/3) Differential Mechanisms of Glutamate Receptor Subtypes in Ischemic Neuronal Death
作者:	許重義(Chung, Y.Hsu);王玉田(Yu-Tian Wang);林欣榮(Shinn-Zong Lin);徐偉成(Woei-Cherng Shyu);李信達(Shin-Da Lee)
贡献者:	醫學院臨床醫學研究所;中國附醫院長室
日期:	2013-07-31
上传时间:	2013-01-25 15:30:35 (UTC+8)
摘要:	中風死因全世界第二位，臺灣第三位，成年人殘障第一主因。血栓溶劑tPA 是治療急性中風唯一有效的藥物，唯受益病人有限，功效不大，並增加腦出血的風險10 倍。開發更安全更有效的中風治療是一個挑戰。本計畫的目標是研究中風後神經元死亡之機制將有助於發展創新的中風治療。中風發生後，缺血區會釋出的大量興奮性神經傳導物質glutamate 使其受體(NMDAR 與AMPAR) 活化，導致興奮性毒性(excitotoxicity)。運用NMDAR 阻斷劑治療並未成功。失敗的主要原因是NMDAR 有多重功能，全面性阻斷有礙腦功能，亦可能造成傷害。我們最近發現次單元之NMDAR (NR2AR) 有利於腦神經細胞存活，而另一次單元之NMDAR (NR2BR) 則媒介神經細胞死亡。本計畫將週詳研究不同glutamte receptor subtypes 在缺血性神經細胞死亡之複雜關連性，成為未來發展創新的中風治療之基礎。子計畫一、研究活化NR2AR 有利神經細胞存活之機制；子計畫二、研究活化 NR2BR 造成神經細胞死亡之機轉；子計畫三、GABA 受體endocytosis 對NR2BR 作用之影響；子計畫四、AMPAR 結合蛋白對excitotoxicity 之影響：子計畫五、中風時glutamate 異常釋放而導致NR2BR 活化之機轉。本計畫都集中在新近glutamate 受體有關的新發現，五個子計畫名有特色創意，經整合而互相連結由五位資深學者參與，另有4 位年青中風研究員加入，各擁有尖端技術的訓練，是全國最好的中風研究團隊。 Ischemic stroke is a major cause of death and disability in Taiwan and around the world. The only therapy for stroke is tPA, a thrombolytic agent, which has a narrow therapeutic window and modest efficacy. tPA therapy is associated with 10-fold increase in the risk of developing serious intracerebral hemorrhage. The primary mechanism of ischemic brain injury is caused by excessive release of glutamate, a major neurotransmitter in the brain, to cause excitotoxicity. Glutamate-induced excitotoxicity is mediated primarily by N-methyl-D-Aspartate receptors (NMDARs). NMDAR blockade has been the major target for developing neuroprotective strategies. Prior works on neutralizing excitotoxicity to reduce ischemic brain injury has been compounded by serious adverse events caused by non-specific blocade of NMDARs. This PPG is on cutting-edge research to explore differential mechanisms of NMDAR subtypes based on recent novel discoveries by members in this PPG team. Emerging evidence suggests that different subtypes of NMDARs mediate different functions by binding to different downstream NMDAR signaling complex. Novel discoveries made by Prof. YT Wang’s group in this PPG team show NR2AR (NR2A-subunit containing NMDAR) binds to NSC (NMDAR Survival signaling Complex). NR2AR is the major NMDAR subtype in the synapses of the adult forebrain. Prof. YT Wang’s group also found that NR2BR (NR2B-subunit containing NMDAR) bind to NDC (NMDAR Death signaling Complex). NR2BR is the major NMDAR subtype in the extrasynaptic sites. These findings raise the possibility that selective NR2BR blockade is neuroprotective and selective NR2AR blockade is detrimental (for overview see Lai TW, Wang YT, Nature Med, 2010 and Martin HG, Wang YT, Cell, 2010). This PPG features 4 senior stroke researchers at China Medical University (CMU) and Prof. YT Wang, an outstandting stroke investigator at the University of Britich Columbia (UBC). These 5 PIs will lead respectively 5 subprojects. Sub-project 1 directed by Prof. CY Hsu is on synaptic NR2A NMDAR activation of the survival signaling complex, aiming to establish the causal role of NR2A subtype of the NMDARs in sustaining neuronal viability. Sub-project 2 directed by Prof. YT Wang is on extrasynaptic NR2B NMDAR activation of the death signaling complex aiming to confirm the pivotal role of NR2B in causing ischemic neuronal death. Sub-project 3 directed by Prof. SD Lee is on GABA receptor endocytosis in excitotoxic depolarization with the major goal of establishing a novel cellular event involving an inhibitory neurotransmitter in an excitotary pathophysiological process. Sub-project 4 directed by Prof. SZ Lin is on AMPA receptor interacting proteins in AMPA receptor-mediated calcium overload, exploring a group of novel proteins in AMPA receptor mechanisms of excitotoxicity. Sub-project 5 directed by Prof. WC Shyu is on regenerative glutamate release during ischemic spreading depression. These 5 inter-related sub-projects are highly focused on glutamate receptor mechanisms in ischemic brain injury covering differential NMDAR subtypes but converging on a common final pathway of excitotoxicity and ischemic neuronal death. Results derived from these highly integrated subprojects will provide novel insights into the development of preventive and therapeutic strategies for stroke.
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