Vascular bridging for neural repair: Oxygen independent induction of the hypoxia response
Funded in: 2017, 2018, 2019, 2020
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Problem: Axons in the spinal cord fail to regenerate
Target: Molecular mechanisms of the cellular response to hypoxia
Goal: A new therapeutic strategy for axonal regeneration
Regrowth of injured nerve fibres (axons) following injury is necessary for regaining the ability to sense and to move. Axons can be injured in both the periphery (following a nerve injury) and in the spinal cord (following spinal cord injury, SCI). In the spinal cord, nerve fibres fail to regenerate unequivocally, and for this reason SCI is a permanent and devastating injury. Even in the periphery, where some regeneration is possible, it is rarely complete, and made even less so by the type of injury and how far axons must regrow. This project seeks to improve axonal regeneration in both the central and peripheral nervous systems by harnessing the hypoxia response – coping mechanisms invoked by cells when oxygen is scarce. We will do so not by changing oxygen levels, but by manipulating key oxygen-sensing molecules, tricking cells into activating responses that will promote regeneration either directly (causing nerve cells to engage their own regenerative machinery) or indirectly (causing the growth of new blood vessels to act as bridges). These oxygen-sensing molecules are called prolyl hydroxylase domain proteins (PHDs). We have mice which have been genetically modified to lack each of these, and in non-modified mice we will use a drug to block all three.
We will examine axon regeneration and recovery of function following
a) moderate nerve injuries (nerve crush which allows for rapid and relatively successful regeneration),
b) severe nerve injuries (nerve cut forming a gap that is more difficult for axons to navigate) and
c) spinal cord injuries (cutting specific tracts responsible for sensation and movement).
In addition, by removing PHD proteins from specific cells or tissues, we will be able to tell in which cells the hypoxia response is most important for successful regeneration. These experiments will allow us to develop a new therapeutic strategy for repairing the damaged nervous system.