Combinatorial approaches – improved axon regeneration?
Funded in: 2013, 2014, 2015, 2016
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Problem: Functional recovery is restricted by the very limited axon regeneration following SCI
Target: Cell autonomous and environmental factors that contribute to axon growth failure
Goal: Effective strategies to promote axon growth and functional recovery after acute and chronic spinal cord injury
Spinal cord injury causes a damage of the neural tissue and axons resulting in the disruption of the connectivity between the CNS and the targets below the injury site. This tissue damage is followed by major functional deficits. For functional recovery it is necessary to re-establish the connectivity and the neural circuits by regrowth of the axons. The regeneration of the axons is a great challenge as mature neurons show only very limited axon regeneration potential. Research into the spinal cord injury has identified both cell autonomous and environmental factors that contribute to axon growth failure.
As environmental factors two major classes of inhibitors are recognized those associated with degenerating myelin (Myelin Associated Inhibitors – MAIs) and with glial scarring (Chondroitin Sulfate Proteoglycans – CSPGs). A critical cell-autonomous factor is the blocked upregulation of growth-associated genes in the CNS resulting in the poor regeneration capacity of neurons. Even if progress has been made in understanding the neuron-intrinsic and extrinsic control of axon growth after central nervous system (CNS) injury, it is not well understood how these factors work in concert to regulate injury-induced axonal growth. Targeting only one molecule or pathway at a time may have limited potential to be an effective therapeutic approach in promoting axon regeneration and functional recovery. It is important to test combinatorial approaches to maximize the therapeutic potential by manipulating both intrinsic and extrinsic factors.
The project will target both the inhibitory CNS environment and the neuron-intrinsic regeneration capacity to increase synergistically axon growth and regeneration. In particular, it will target
- Nogo, a myelin associated inhibitor
- CSPGs, an inhibitor associated with glial scarring
- PTEN, an intracellular inhibitor
The combinatorial approaches to maximize the therapeutic potential by manipulating both intrinsic and extrinsic factors will be tested in acute spinal cord injury as well as in chronic spinal cord injury. Using both acute and chronic spinal cord injury models, the proposed research aims to develop more effective strategies to promote axon growth and functional recovery after severe spinal cord injuries