Stephen Strittmatter, Yale University School of Medicine, Program in Cellular Neuroscience, Neurodegeneration and Repair, New Heaven, USA

Recovery from Spinal Cord Injury through altered Phosphoinositide Metabolism

Funded in: 2013, 2014, 2015

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Problem: The poor ability of mature axons to regenerate

Target: The phosphatase (Inpp5f) as an intracellular inhibitor of axon regeneration 

Goal: Improvement of the intrinsic axon growth potential

Spinal cord injury (SCI) causes major and persistent disability due to the disruption of the axons and the connectivity between the brain and the muscles below the lesion. The regeneration of mature axons is very poor as adult CNS neurons lose their axon growth ability. To date the limited axon regeneration of injured adult CNS is a major restriction for functional recovery and one of the great challenges of spinal cord injury (SCI) research.

Dr. Strittmatter’s team developed a screen for endogenous genes limiting the regeneration of axons in the mature mammalian CNS to find molecular target signals responsible for the poor regeneration capacity.
Preliminary studies using those screening methods identified the phosphatase Inpp5f as an intracellular inhibitor of axon regeneration. And preliminary data in-vitro and in an in-vivo optic nerve injury model in vivo support the role of Inpp5f in limiting axonal regeneration.

This project now will

  • examine whether a knock down of this phosphatase (Inpp5f)  in neurons result in an improved regeneration of axons in the spinal cord supporting  functional recovery. The study will be done in a thoracic dorsal spinal cord hemisection, outcomes will be axon tracing, behavior and gait kinematic analysis.
  • explore the mechanism of action (and intracellular targets) of Inpp5f in regulating axonal growth.

The results from this project may lead in the future to the development of small molecules targeting the Inpp5f which could improve the intrinsic axon growth potential.