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UBC Theses and Dissertations

Hypoxia mimicry for enhancing regeneration and functional recovery following peripheral nerve injury Smaila, Brittney


Peripheral nerve injuries (PNIs) occur in 1-3% of patients with any trauma. While peripheral axons have the ability to regenerate at ~1-3 mm/day, the distance over which they must do so means lengthy recovery times associated with regenerative failure due to a decline in supporting cells’ ability to maintain axon growth. Successful axonal regeneration depends heavily upon the neuronal response to injury, and that of myeloid cells recruited to the damaged nerve. In injured regeneration-competent neurons, the transcriptomic changes that occur mirror those observed in hypoxia; hypoxia inducible factors (HIFs) effect some of these. HIF activity is governed in turn by the HIF-hydroxylases, prolyl hydroxylase domain (PHD) proteins and factor inhibiting HIF (FIH). Under normoxic conditions, HIF-hydroxylases act as master regulators of the hypoxia response, targeting HIFs for proteasomal degradation. I hypothesized that deleting any or all of the PHDs (PHD1, 2, and 3), or inhibiting PHDs pharmacologically, would induce a hypoxia response and enhance axonal regeneration and functional recovery following PNI. I used global PHD1 knockout, global PHD3 knockout, and heterozygous PHD2 transgenic mice, as well as non-transgenic mice treated with dimethyloxalylglycine (DMOG), a pan-HIF-hydroxylase inhibitor. Using sciatic nerve models of injury, I assessed functional recovery at various time points post-injury using behavioural assays. I characterized macrophage and axon densities in the nerves after injury and assessed DMOG-induced changes in macrophage phenotype using FACS, RT-PCR and immunohistochemistry. I found that deletion of PHD1 or PHD3, or inhibition of all three PHDs resulted in earlier functional recovery after injury, increased macrophage infiltration in the injured nerve, an M2-skewed macrophage phenotype, and enhanced axonal regrowth. Additionally, deletion of any of the PHDs, or their inhibition by DMOG, resulted in improved electromyographical responses of the nerve one-month post-injury. These findings suggest that nerve repair can be aided by hypoxia-independent induction of the hypoxia response.

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