Mechanisms Driving Regenerative Neurogenesis in Planarians

项目摘要 人类的大脑和脊髓组织再生能力很差。无法再生 缺失或受损的细胞阻碍了神经退行性疾病后的存活和恢复 疾病、中风、创伤性或缺血性损伤或发育错误。与人类不同， 其他动物可以有效地修复中枢神经系统内的严重损伤或损害， 神经系统自由生活的淡水扁虫称为真涡虫， 非凡的再生能力，包括完美的再生和替换 所有的大脑和神经组织在组织损失或损伤后， 现有的组织和使用成人多能干细胞来取代不同的细胞类型， 包括几十种神经元。Planarians创造神经元在适当的比例 然后将神经元重新排列并连接到目标以恢复功能。长期 目的是发现强大的神经再生的分子和细胞基础， 真涡虫为实现这一目标，第一个具体目标是确定和描述 多能干细胞再生神经发生的重要因素， 首先是多巴胺能神经元的再生。四个转录因子编码基因 对于多巴胺能神经元亚型再生和维持重要的是， 已经被发现了。以下具体目标将提供重要信息 关于环境因素如何通过多能干细胞促进大脑再生， vivo.第二个具体目的是检验神经发生被上调的假设 通过创伤诱导的信号机制。第三 一个特别的目的是检验这一假说，即涡虫神经发生是由极性驱动的 提示，以便在适当的位置创建正确类型的新神经元。的 本申请中提出的工作在概念上是创新的，因为使用了 高度再生模式生物，以探索再生神经发生，因为 开发新的分子和行为分析（例如DAP-Seq，活猎物 测定）。这项研究具有重要意义，因为它将提供一个基础 理解成功的神经再生对损伤的反应，长期 目标是确定可以利用的途径或分子机制， 改善人类再生疗法。

Project Summary Humans regenerate tissue of the brain and spinal cord poorly. Failure to regenerate missing or damaged cells impedes survival and recovery after neurodegenerative disease, stroke, traumatic or ischemic injury, or developmental error. Unlike humans, other animals can effectively repair dramatic injuries or damage within the central nervous system. Free-living freshwater flatworms called planarians possess extraordinary regenerative abilities, including flawless regeneration and replacement of all brain and nerve cord tissues. After tissue loss or damage, planarians remodel existing tissue and use adult pluripotent stem cells to replace diverse cell types, including dozens of types of neurons. Planarians create neurons in appropriate ratios and then repattern and reconnect neurons to targets to restore function. The long-term goal is to discover the molecular and cellular basis of robust neural regeneration using planarians. Toward that objective, the first specific aim is to identify and characterize factors important for regenerative neurogenesis from pluripotent stem cells, focusing first on regeneration of dopaminergic neurons. Four transcription factor-encoding genes important for regeneration and maintenance of dopaminergic neuron subtypes have already been discovered. The following specific aims will provide critical information about how environmental cues promote brain regeneration by pluripotent stem cells in vivo. The second specific aim is to test the hypothesis that neurogenesis is upregulated in planarians after injury, through wound-induced signaling mechanisms. The third specific aim is to test the hypothesis that planarian neurogenesis is driven by polarity cues so that new neurons of the correct types are created in the proper locations. The proposed work in this application is conceptually innovative because of the use of a highly regenerative model organism to explore regenerative neurogenesis and because of the development of new molecular and behavioral assays (e.g. DAP-Seq, live prey assays). The proposed research is significant because it will provide a foundational understanding of successful neural regeneration in response to injury, with a long-term goal of identifying pathways or molecular mechanisms that could be leveraged to improve human regenerative therapies.