Targeted strategies to improve regeneration in the injured CNS

As we progress in deciphering the pathways regulating axon regeneration in peripheral sensory neurons, we are testing whether manipulating neurons and non-neuronal cells — genetically or pharmacologically — enhances axon regeneration in the CNS, using both the spinal cord and the optic nerve injury models.

We found that activation of the PPARα signaling pathway in SGCs, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. Interestingly, fenofibrate was shown in clinical trials to have neuroprotective effects in diabetic retinopathy and traumatic brain injury.

We also determine if findings related to injury responses made in the mouse model system are relevant to human physiology. We pursue these studies using human DRG tissue in collaboration with Dr. Robert Gereau in the Department of Anesthesiology, who developed the use of human sensory neurons from organ donors to enhance the translational relevance of preclinical studies on pain and regeneration. Our results indicate that genes enriched in SGCs related to lipid metabolism and PPARα signaling are conserved between mouse, rat and human. We will expand these studies to multiple human samples of both sexes and determine the extent to which the transcriptional profile of multiple cell types and cell-cell interactome is conserved between mouse and human.

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