CHARACTERIZATION OF GDNF ALPHA 1 (GFR ALPHA 1) RECEPTOR IN STROKE

中风时 GDNF ALPHA 1 (GFR ALPHA 1) 受体的特征

• 批准号: 6431949
• 负责人: BARRY J. HOFFER
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431949
• 关键词: GABA receptor; calcium binding protein; cell line; cell type; gene expression; genetic regulation; glutamine; growth factor receptors; hippocampus; interneurons; laboratory mouse; laboratory rat; neurotrophic factors; protein localization; pyramidal cells; substantia nigra; tissue /cell culture

Glial cell line derived neurotrophic factor (GDNF) promotes neuronal survival in vitro and in vivo. Previous studies have shown that intracerebral administration of GDNF reduces infarction in the cortex (Wang et al. 1997) induced by middle cerebral artery occlusion (MCA-O) and subsequent reperfusion. The participation of endogenous GDNF during stroke has been suggested from northern blot analysis showing that GDNF transcripts are induced one hour after reperfusion (Abe et al. 1997). GDNF exerts its biological activity by binding to its receptor GFR a-1 and transferring its signal through c-ret. Thus, we evaluate possible changes in GFR a-1 and c-ret expression in a rat model of stroke produced by MCA-O. Using in situ hybridization, we detected upregulation of GFR a-1 expression in cortex, dentate gyrus and hippocampus. The peak of expression was 6-12 hrs after reperfusion. Interestingly, c-ret expression was also upregulated in cortex and hippocampus but 12-24 hrs after reperfusion. In normal adult rat brain, GFR a-1 expression in hippocampus is associated with parvalbumin immunoreactive neurons. We are currently investigating the phenotypic population of the cells that undergo preferential upregulation of GFR a-1 and c-ret after MCA-O. This information will permit better understanding the cellular components that participate in the effects of GDNF during stroke.

胶质细胞源性神经营养因子（GDNF）在体外和体内促进神经元存活。先前的研究已经表明，脑内给予GDNF减少了由大脑中动脉闭塞（MCA-0）和随后的再灌注诱导的皮质梗塞（Wang等，1997）。北方印迹分析表明，GDNF转录物在再灌注后1小时被诱导，这表明内源性GDNF参与了中风过程（Abe等，1997）。GDNF通过与受体GFR a-1结合并通过c-ret传递信号而发挥其生物学活性。因此，我们评估了可能的变化，GFR α-1和c-ret表达的大鼠模型中产生的MCA-O中风。采用原位杂交技术，我们检测到GFRa-1在皮层、齿状回和海马的表达上调。表达高峰在再灌注后6-12小时。有趣的是，c-ret表达也上调，但在再灌注12-24小时后，在皮层和海马。在正常成年大鼠脑中，海马中的GFR α-1表达与小白蛋白免疫反应性神经元相关。我们目前正在研究在MCA-0后经历GFR a-1和c-ret优先上调的细胞的表型群体。这一信息将允许更好地了解参与脑卒中期间GDNF作用的细胞成分。