B-RAF activation as a way to enhance regeneration in the injured spinal cord
Funded in: 2014, 2015, 2016
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Problem: Inhibitory molecules in adult spinal cord and decrease of intrinsic axon growth capacity in adult nerve cells especially in the central nervous system (CNS) inhibit axonal regrowth after spinal cord injury.
Target: B-RAF alone, or in combination with PTEN to promote axon regeneration.
Goal: Enhance the low intrinsic axon growth capacity.
Spinal cord injury causes paralysis because neuronal connections are severed. To achieve functional recovery, at the most basic level, injured nerve cells need to re-grow their axons to bridge the injury before neuronal circuits can be reconnected. Axons grow quickly and easily in the spinal cord during fetal development, but hardly at all in the adult. This lack of axon re-growth is attributed to two principal reasons:
first, the abundance of inhibitory molecules in adult spinal cord and
second, a sharp decrease of intrinsic axon growth capacity in adult nerve cells especially in the central nervous system (CNS).
Therefore, it will be necessary to both counteract growth inhibitory molecules and enhance the low intrinsic axon growth capacity to enable productive axon regeneration in the spinal cord.
Activation of B-RAF signaling pathway alone enables regenerative axon growth in the optic nerve following a crush injury, as well as strong re-growth of lesioned sensory axons into the spinal cord after a dorsal root crush. Moreover, the combination of two signaling pathways (B-RAF gain-of-function and PTEN loss-of-function), promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. The project plans to test the effects of elevated RAF signaling alone and in combination with activation of the PI3 kinase-mTOR pathway (PTEN). Maximizing the capacity of regenerative axon growth is likely to require a combinatory approach, plus possibly other growth mediators and/or inhibitors of anti-growth signals. This approach will provide a rationale for the development of new clinical interventions for spinal cord injury patients.