Astrocyte-mediated neuroprotection after CNS injury

中枢神经系统损伤后星形胶质细胞介导的神经保护

• 批准号: 6679822
• 负责人: ROBERT J MCKEON
• 金额: $ 28.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6679822
• 关键词: astrocytes; biological transport; cell death; central nervous system; cerebral ischemia /hypoxia; disease /disorder model; genetically modified animals; glutamates; immunocytochemistry; injury; laboratory mouse; neurons; neuroprotectants; polymerase chain reaction; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The astrocytic response to CNS injury is complex and multifaceted, with important implications for protecting vulnerable neurons from cell death. Although specific neuroprotective functions of astrocytes, e.g., glutamate transport, are known to be energy dependent, little is known about how, or if, astrocytes alter their bioenergetic state in response to injury. We have discovered that expression of the Adenine Nucleotide Translocator-1 (Ant1) by reactive astrocytes increases after cortical injury and that this increase is mediated by the injury-induced cytokine transforming growth factor beta1(TGF-beta1). Ant1 is an inner mitochondrial membrane protein that exchanges mitochondrial ATP for cytosolic ADP, thereby regulating the supply of the substrate required for continued mitochondrial energy production (ADP) as well as the delivery of ATP to the cytosol for energy dependent functions. Importantly, the expression of the closely related isoform, Ant2, does not appear to change. Additional preliminary data demonstrate that glutamate uptake by Ant1 null astrocytes is significantly impaired and that Ant1 null mutant animals are prone to cortical damage following combined hypoxic/ischemic injury. These data suggest that reactive astrocytes experience a bioenergetic demand and are consistent with the hypothesis that Ant1 is a critical component of the astrocytic response to injury by mobilizing the energy required during reactive astrogliosis. This hypothesis will be tested in vitro and in an in vivo model of cerebral hypoxic/ischemic injury in Ant1 null mutant, Ant2 neural null transgenic, and genetically matched control mice. To test this hypothesis, we will: (1) examine whether astrocytic Ant1 is required to protect neurons from excitotoxic injury or death in vitro, by focusing on the critical astrocytic function of glutamate uptake; and (2) determine if astrocytic Ant1 expression is required for neuronal survival in vivo after hypoxic/ischemic injury. These studies will provide important mechanistic insight into the biological response of reactive astrocytes by examining the requirement for a molecule that facilitates mitochondrial ATP production and mobilization.

描述（由申请人提供）：对中枢神经系统损伤的星形细胞反应是复杂且多方面的，对保护脆弱的神经元免受细胞死亡的影响而具有重要意义。尽管已知星形胶质细胞（例如谷氨酸转运）的特定神经保护功能是能量依赖性的，但对于响应损伤而改变了星形胶质细胞如何改变其生物能状态。我们已经发现，皮质损伤后反应性星形胶质细胞增加腺嘌呤核苷酸易位剂1（ANT1），并且这种增加是由损伤诱导的细胞因子转化生长因子Beta1（TGF-BETA1）介导的。 ANT1是一种内部线粒体膜蛋白，可将线粒体ATP交换为胞质ADP，从而调节持续线粒体能量产生（ADP）所需的底物的供应，以及将ATP递送到cytosol的能量功能。重要的是，密切相关的同工型ANT2的表达似乎没有改变。其他初步数据表明，ANT1无效星形胶质细胞的谷氨酸摄取显着受损，并且在缺氧/缺血性损伤组合后，ANT1无效的动物容易受到皮质损伤。这些数据表明，反应性星形胶质细胞经历了生物能量需求，并且与假设ANT1是通过动员反应性星形胶质细胞膜过程中所需的能量来假设是星形胶质细胞反应的关键组成部分。该假设将在ANT1无效突变体，ANT2神经无效转基因和基因相匹配的对照小鼠的体外和体内模型中进行测试。为了检验该假设，我们将：（1）检查是否需要通过关注谷氨酸摄取的关键星形胶质细胞功能来保护神经元免受兴奋性毒性损伤或体外死亡的影响； （2）确定在缺氧/缺血性损伤后体内神经元存活是否需要星形细胞ANT1表达。这些研究将通过研究促进线粒体ATP产生和动员的分子的需求，从而为反应性星形胶质细胞的生物学反应提供重要的机理洞察力。