Deciphering the molecular networks that govern the neurogenic potential of astrocytes in the adult mouse brain

破译成年小鼠大脑中控制星形胶质细胞神经源性潜力的分子网络

• 批准号: 390962667
• 负责人: Dr. Michael Ratz
• 金额: --
• 依托单位: Institutionen för Cell- och Molekylärbiologi
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390962667?language=en
• 关键词: Deciphering; molecular; networks; govern; neurogenic

The adult mammalian brain contains specialized astrocytes that act as neural stem cells capable of generating functional neurons throughout life. However, due to the anatomical restriction of constitutive adult neurogenesis to a few neurogenic regions, the brain has only a limited capacity to regenerate. It was recently discovered that astrocytes in the striatum of adult mice possess an intrinsic capacity to generate new neurons in vivo after stroke or attenuation of Notch signaling. While the induction of neurogenesis from striatal astrocytes could provide new avenues for brain repair on the long term, the molecular and cellular mechanisms that govern the process need to be explored first. Here, I propose to use innovative molecular tools to investigate the cell-intrinsic and extracellular networks that govern fate decisions of striatal astrocytes in vivo. First, I will provide an innovative solution to combine CRISPR-based endogenous barcode generation with in situ single cell RNA-seq readout. Second, I will use this approach to reconstruct astrocyte lineages and to identify the underlying transcriptional networks within an anatomical context. Third, based on the obtained insights, I will employ in vivo CRISPR gene editing in adult mice to manipulate the molecular logic underlying fate decisions in striatal astrocytes in order to generate a cell lineage of desire. My approach will yield a comprehensive view on the molecular and cellular networks that govern in vivo neurogenesis from striatal astrocytes and intends to provide new routes for neuronal repair strategies.

成年哺乳动物的大脑中含有专门的星形胶质细胞，它们作为神经干细胞能够在整个生命过程中产生功能性神经元。然而，由于组成性成人神经发生的解剖学限制，少数神经发生区域，大脑只有有限的再生能力。最近发现，成年小鼠纹状体中的星形胶质细胞具有在中风或Notch信号转导减弱后体内产生新神经元的内在能力。虽然从纹状体星形胶质细胞诱导神经发生可以为长期的脑修复提供新的途径，但需要首先探索管理该过程的分子和细胞机制。在这里，我建议使用创新的分子工具来研究细胞内和细胞外网络，在体内纹状体星形胶质细胞的命运决定。首先，我将提供一种创新的解决方案，将基于联合收割机的内源性条形码生成与原位单细胞RNA-seq读出相结合。其次，我将使用这种方法来重建星形胶质细胞谱系，并确定在解剖学背景下的基础转录网络。第三，基于所获得的见解，我将在成年小鼠中采用体内CRISPR基因编辑来操纵纹状体星形胶质细胞中命运决定的分子逻辑，以产生期望的细胞谱系。我的方法将产生一个全面的看法，在体内纹状体星形胶质细胞神经发生的分子和细胞网络，并打算提供新的途径神经元修复策略。