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.

Public Health Relevance

Traumatic brain injury causes a huge financial and emotional burden to patients and their caregivers in the US. There currently is no effective cure due to a permanent loss of neurons and the disruption of neuronal circuitry. The proposed studies will define a novel chemical approach to reprogram brain injury for neuronal regeneration and functional recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099073-03
Application #
9706656
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
2017-06-15
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Wang, Lei-Lei; Zhang, Chun-Li (2018) Engineering new neurons: in vivo reprogramming in mammalian brain and spinal cord. Cell Tissue Res 371:201-212
Chen, Chunhai; Zhong, Xiaoling; Smith, Derek K et al. (2017) Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury. Cereb Cortex :1-16
Tang, Yu; Liu, Meng-Lu; Zang, Tong et al. (2017) Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons. Front Mol Neurosci 10:359