Therapeutic Potential of Protein Kinases and Their Downstream Targets Following Traumatic Cervical Spinal Cord Injury
Despite recent advances in the management and characterization of traumatic spinal cord injury (SCI), the current therapeutic options for patients remain limited. The SCI-induced cellular response is mediated through series of protein kinases, which are a group of globular proteins that reversibly phosphorylate downstream substrates to alter the transcriptional patterns of local and surrounding cells. While these altered kinase activities at the cellular level represent compelling targets for therapeutic intervention, the specific function of different kinase pathways is yet to be investigated. The objective of this doctoral thesis is to elucidate the role of protein kinases in injury progression and explore their therapeutic potential following traumatic cervical SCI. First, a comparative cross-species transcriptional and genomic analysis identified molecular pathways with great therapeutic potential and translational relevance. As these molecular targets were predominantly kinase-related, the subsequent experiments were aimed to assess the efficacy of a clinically approved protein kinase inhibitor—midostaurin—to alleviate secondary pathogenesis. While the results showed great promise, more targeted strategies would be necessary to minimize off-target effects and enhance effectiveness. Hence, gene therapy was used to modulate a downstream target of protein kinases, which demonstrated that restoring KCC2 activity can enhance functional recovery. This work demonstrates the importance of targeted kinome-based therapeutics to alter the secondary response following traumatic SCI.
Cross-Species Comparison, KCC2, Kinome, Spinal Cord Injury
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