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Role of soluble adenylyl cyclase in ischemia-reperfusion-induced brain injury

可溶性腺苷酸环化酶在缺血再灌注脑损伤中的作用

基本信息

批准号：
165505620
负责人：
Privatdozent Dr. Yury Ladilov
金额：
--
依托单位：
Department of Endocrinology
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/165505620?language=en
关键词：
Role soluble adenylyl cyclase ischemia

项目摘要

Ischemic stroke is an acute neurodegenerative disorder that is one of the leading causes of death and disability. Increasing evidence suggest that apoptosis contributes significantly in the neuronal death under cerebral ischemia-reperfusion. Within several signaling pathways, cAMP-PKA signaling plays an essential role in modulating the apoptotic response to different stress stimuli including ischemic insult. Until now, it was attributed exclusively to the activity of the G-protein-responsive transmembrane adenylyl cyclase (tmAC). Aside from the tmAC, mammalian cells possess a second source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC). Recently, we demonstrated that this cyclase is an essential modulator of mitochondria-dependent apoptosis in coronary endothelial cells. Furthermore, we found that the active form of this cyclase is also expressed in rat cortex. Whether sAC contributes in apoptosis of neuronal cells is unknown. To investigate the role of sAC in cerebral apoptosis induced by ischemia-reperfusion is the aim of the proposed project. For this purpose, first in vitro studies with primary rat embryonic cell culture as well as with human neuroblastoma culture exposed to simulated ischemia-reperfusion will be performed. Finally, in vivo studies with wild type or sAC-knockout mice will be curried out.

缺血性中风是一种急性神经退行性疾病，是导致死亡和残疾的主要原因之一。越来越多的证据表明，细胞凋亡在脑缺血再灌流后神经元死亡中起重要作用。在多种信号通路中，cAMP-PKA信号在调节细胞对包括缺血损伤在内的不同应激刺激的凋亡反应中起着至关重要的作用。到目前为止，它完全归因于G蛋白反应性跨膜腺苷酸环化酶(TMAC)的活性。除了TMAC外，哺乳动物细胞还有第二种cAMP来源，即普遍表达的可溶性腺苷环化酶(SAC)。最近，我们证实该环化酶是冠脉内皮细胞线粒体依赖性细胞凋亡的重要调节因子。此外，我们还发现该环化酶的活性形式在大鼠皮质中也有表达。SAC是否参与神经细胞的凋亡尚不清楚。本研究的目的是探讨SAC在脑缺血再灌流诱导的脑细胞凋亡中的作用。为此，首先将进行原代大鼠胚胎细胞培养以及暴露于模拟缺血-再灌注的人神经母细胞瘤培养的体外研究。最后，野生型或SAC基因敲除小鼠的体内研究将被搁置。