Cellular Dynamics and Regulatory Pathways for Successful Regeneration

成功再生的细胞动力学和调控途径

• 批准号: 497789076
• 负责人: Professorin Dr. Magdalena Götz
• 金额: --
• 依托单位: Institut für Physiologische Genomik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497789076?language=en
• 关键词: Cellular; Dynamics; Regulatory; Pathways; Successful

The recovery of neuronal functions after different types of brain injuries is one of the most common healthcare challenges, yet without successful therapies. Injury induced glial scar is the prime reason for the poor recovery, as the scar does not only interfere with the function of the brain area at the site of its deposition, but also hampers integration of new neurons. In contrast to mammals, zebrafish can restrict glial scar formation, activate neurogenic potential of glial cells to generate new neurons and regenerate neural tissue in a scarless manner. Therefore, we propose to pursue a novel trans-species comparison (zebrafish and mouse) using single cell transcriptomes to identify the cellular trajectories defining the glial reaction in zebrafish and mouse brain, with the goal of eliminating its detrimental effects, while at the same time not hampering the initial beneficial role of glial cells in wound healing. Moreover, this comparison will allow us to identify the cellular states prone for direct reprogramming of glial cells to neurons, as a mean for functional regeneration in the mammalian brain. The second set of experiments will aim at identification of cellular possible cellular interactions of the neuroinflammatory cells (microglia and astrocytes) and transplanted or in situ reprogrammed neurons as a mean to improve their survival and differentiation into proper neuronal subtypes necessary for the functional recovery.

不同类型脑损伤后神经元功能的恢复是最常见的医疗挑战之一，但目前尚无成功的治疗方法。损伤引起的神经胶质疤痕是恢复不良的主要原因，因为疤痕不仅干扰其沉积部位的大脑区域的功能，而且还阻碍新神经元的整合。与哺乳动物相比，斑马鱼可以限制神经胶质疤痕的形成，激活神经胶质细胞的神经原性潜力，产生新的神经元，并以无疤痕的方式再生神经组织。因此，我们建议利用单细胞转录组进行一种新颖的跨物种比较（斑马鱼和小鼠），以识别定义斑马鱼和小鼠大脑中神经胶质反应的细胞轨迹，目的是消除其有害影响，同时不妨碍神经胶质细胞在伤口愈合中最初的有益作用。此外，这种比较将使我们能够识别容易将神经胶质细胞直接重编程为神经元的细胞状态，作为哺乳动物大脑功能再生的手段。第二组实验旨在鉴定神经炎症细胞（小胶质细胞和星形胶质细胞）与移植或原位重编程神经元之间可能的细胞相互作用，作为提高其存活率和分化为功能恢复所需的适当神经元亚型的手段。