Improving axonal regeneration after spinal cord injury by potentiating the dual leucine zipper kinase pathway
Funded in: 2013, 2014, 2015
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Problem: Neurons of the central nervous system do not regenerate as well as those of the peripheral nervous system.
Target: The molecule DLK (dual leucine zipper kinase) as activator of the pro-regenerative program in the cell
Goal: Boost the regeneration capacity of central nervous system neurons
Spinal cord injury (SCI) causes major and persistent disability due to the disruption of the axons and the connectivity between the brain and their targets below the lesion. To date the limited axon regeneration of injured adult CNS is one of the great challenges of spinal cord injury (SCI) research.
Axons in the adult central nervous system (CNS) fail to regenerate following injury whereas peripheral axons can re-grow to their targets. This difference is attributable to two main factors:
- first, CNS axons must overcome the extrinsic inhibitory environment of the CNS, and
- second, an injury of the peripheral axon can activate a neuron-intrinsic gene expression program that allows for robust axonal re-growth (“preconditioning injury”)
Previous studies suggest that in the sensory neurons the molecule DLK plays the essential role for the response to the preconditioning injury. The project will explore the function of DLK and manipulate its activity to assess whether DLK is necessary for the ability of a preconditioning lesion (i.e. sciatic nerve lesion) to activate the pro-regenerative program and improve axonal regeneration.
In sum, this proposal will study the involvement of the DLK pathway in axon regeneration after SCI and test new strategies to improve axon regeneration and functional recovery after SCI.