Integrins enhance CNS regeneration but can be inactivated in injury sites, including chondroitin sulfate proteoglycans (CSPGs). Enzymes which counteract CSPGs also enhance CNS regeneration, likely through integrin-dependent mechanisms.
Following spinal cord injury (SCI), axons do not regenerate. Integrins have been shown to promote axonal regeneration giving rise to promising results for SCI repair. Specifically, re-expression of the alpha9 integrin subunit that binds to tenascin-C (TN-C), an extracellular matrix glycoprotein highly upregulated post-injury, has been shown to rescue injury-induced inhibition of axonal growth. Likewise, the activation state of integrins is critical, as inactive integrins do not regenerate damaged axons. Furthermore, molecules within an SCI lesion such as chondroitin sulphate proteoglycans (CSPGs) inactivate integrins. For many years, studies have shown that CSPG-growth inhibition can be rescued with application of the enzyme chondroitinase ABC (cABC), an enzyme which digests inhibitory glycosaminoglycan side chains of CSPGs. This rescue effect is likely integrin dependent whereas cABC is likely to maintain or return the integrin into an activated (growth-promoting) state.
The objective of this project is determine whether cABC treatment can both decrease the inhibitory extracellular environment while relieving the inhibitory signalling that reduces integrin activation, thus acting to amplify alpha9 integrin-mediated neurite growth and axonal regeneration in the injured spinal cord.
Principal investigator: Melissa R. Andrews
Funding provider: International Foundation for Research in Paraplegia
Funding dates: December 1, 2020 – November 30, 2022