Modulation of AMPK as a candidate novel regenerative pathway after SCI
Funded in: 2016, 2017, 2018
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Problem: Axonal regeneration in the central nervous system (CNS) after a spinal cord injury (SCI) fails
Target: Modulation of the AMPK-dependent pathway
Goal: A novel strategy to enhance axonal regeneration and functional recovery
Axonal regeneration in the peripheral nervous system (PNS) occurs and this is associated with partial functional recovery. On the contrary, axonal regeneration in the central nervous system (CNS) such as after a spinal cord injury (SCI) fails, strongly contributing to unsuccessful functional recovery. However, despite recent progress, we are still uncovering the nature of these contrasting molecular signatures associated with successful PNS versus failed CNS regeneration, limiting the identification of effective targets for nerve regeneration. To this end, we have recently performed combined systematic genome wide gene and protein expression experiments in mice following PNS versus spinal CNS injury.
These experiments allowed identifying that energy metabolism via the protein kinase AMPK is reduced in the presence of nerve regeneration while it remains unchanged after spinal cord injury. The aims of this proposal expand upon these data and are two fold, mechanistic and phenotypic in terms of regeneration and recovery after SCI:
- Elucidate the mechanisms responsible for AMPK-dependent inhibition after sciatic regenerative versus spinal non-regenerative nerve injury.
- Investigate the ability of pharmacological and genetic AMPK inhibition to enhance axonal regeneration and function of ascending sensory fibers in the injured spinal cord. Both genetic and pharmacological intervention aim to provide a translational opportunity with the aim to enhance dorsal column axonal regeneration and functional recovery after spinal cord injury.
Ultimately, these studies may lead to the genetic and pharmacological targeting of AMPK-dependent pathway as a novel strategy to enhance axonal regeneration and functional recovery after SCI.