Chemical Reprogramming of Traumatic Brain Injury

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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.