Chemical Reprogramming of Traumatic Brain Injury

总结 创伤性脑损伤经常导致神经元的损失和神经回路的中断。一项基本 但尚未解决的挑战是如何恢复失去的神经元和修复成人大脑受损的神经回路。 神经干细胞在成人大脑中持续存在并产生新的神经元;然而，它们非常有限的定位 使其不足以用于再生目的。移植干细胞的功效受到 诱导神经元的存活和整合，以及潜在的肿瘤发生。长期目标是 一项提案是为脑损伤定义一种新的再生策略，即利用患者的内源性神经胶质细胞， 没有移植的细胞这一策略是基于我们最近的工作表明，常驻神经胶质细胞可以 在成年小鼠大脑中转录重编程为新的神经元。这些重新编程的神经元可以 变得成熟并在功能上整合到局部神经元网络中。我们的初步数据进一步显示 在创伤后，成年人大脑中的一群小分子也可以诱导新的神经元， 这表明化学生物学可以应用于体内神经重编程。提出了三个目标， 本申请进一步分析了化学重编程过程：1）优化化学成分 并了解潜在的分子机制，2）检查细胞起源，成熟和连接 成年小鼠脑损伤后化学诱导的新神经元，以及3）确定生物学效应 化学重编程对脑损伤后行为恢复的影响。这个概念验证的结果 这项研究将为设计一种可能改变模式的脑损伤治疗策略奠定基础。

SUMMARY Traumatic brain injury frequently leads to a loss of neurons and the disruption of neural circuitry. A fundamental but unresolved challenge is how to restore lost neurons and repair the damaged neural circuits of the adult brain. Neural stem cells persist and generate new neurons in the adult brain; however, their very restricted localization renders them inadequate for regenerative purposes. The efficacy of transplanted stem cells is limited by the survival and integration of induced neurons, as well as, a potential for tumorigenesis. The long-term goal of this proposal is to define a new regenerative strategy for brain injury, which is to use a patient's endogenous glial cells without transplantation. This strategy is based on our recent work showing that resident glial cells can be transcriptionally reprogrammed into new neurons in the adult mouse brain. These reprogrammed neurons can become mature and functionally integrate into the local neuronal network. Our preliminary data further revealed that new neurons can also be induced by a pool of small molecules in the adult brain after traumatic injury, suggesting that chemical biology can be applied to neural reprogramming in vivo. Three aims are proposed in this application to further analyze the chemical reprogramming process: 1) to optimize the chemical composition and to understand the underlying molecular mechanisms, 2) to examine cell origin, maturation, and connectivity of chemically induced new neurons in the adult mouse brain after injury, and 3) to determine the biological effect of chemical reprogramming on behavioral recovery after brain injury. The results of this proof-of-concept research will lay the ground work for devising a potentially paradigm-shifting therapeutic strategy for brain injury.