Mechanisms Driving Regenerative Neurogenesis in Planarians

项目摘要 人类大脑和脊髓组织的再生能力很差。再生失败 神经退行性变后细胞缺失或受损阻碍生存和恢复 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央脑内戏剧性的损伤或损害 神经系统。自由生活的淡水扁虫，称为平面动物，拥有 非凡的再生能力，包括完美的再生和更换 所有的脑组织和神经索组织。在组织丢失或损坏后，平面动物进行重塑 并使用成年多能干细胞来取代不同类型的细胞， 包括几十种类型的神经元。行星动物以适当的比例创造神经元 然后重塑模式并将神经元与靶细胞重新连接以恢复功能。长期的 目标是发现强健的神经再生的分子和细胞基础 行星类动物。为了实现这一目标，第一个具体目标是确定和确定 多能干细胞再生神经发生的重要因素 首先是关于多巴胺能神经元的再生。四个转录因子编码基因 对多巴胺能神经元亚型的再生和维持很重要 已经被发现了。以下具体目标将提供关键信息 关于环境线索如何促进脑再生的多能干细胞在 活着。第二个具体目标是检验神经发生上调的假说。 在损伤后的浮游生物中，通过创伤诱导的信号机制。第三 其具体目的是验证这样一种假设，即脊椎动物的神经发生是由极性驱动的。 这样才能在正确的位置产生正确类型的新神经元。这个 本申请中提议的工作在概念上是创新的，因为使用了 高度再生的模式生物来探索再生神经发生，因为 开发新的分子和行为分析方法(例如DAP-Seq、活猎物 化验)。这项拟议的研究具有重要意义，因为它将为 对损伤后成功的神经再生的理解，具有长期的 目标是确定可以利用的途径或分子机制 改进人类再生疗法。

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.