Modulating the extracellular matrix to induce axon regrowth and recovery after spinal cord injury
Funded in: 2018, 2019, 2020
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Problem: The degree of plasticity and regeneration in the adult central nervous system (CNS) is limited
Target: The inhibitory effect of CSPGs chondroitin sulfate proteoglycans (CSPGs)
Goal: To reverse the CSPG effect from inhibition to activation of regrowth by CSPG binding proteins
Introduction: The limited degree of plasticity and regeneration in the adult central nervous system (CNS) is reflected in failure to grow neurites (axons and dendrites) across the injured area, which causes a major medical problem in traumas of the spinal cord. The extracellular matrix (ECM) of the central nervous system and its chondroitin sulfate proteoglycans (CSPGs) in the glial scar are currently regarded as major inhibitory regulators of plasticity and regeneration.
Hypothesis: The role of the CSPG-rich matrix can be reversed from inhibition to activation of regenerative neurite growth. According to this paradigm shift, the juvenile plasticity and regeneration enhancing property can be restored in the adult mammalian CNS using the CSPG-binding protein HB-GAM (heparin-binding growth-associated molecule; also designated as pleiotrophin) that is highly expressed in the juvenile CNS but is essentially lost upon adulthood.
Research models and methods: We use CSPG substrates to model neurite regrowth in CNS neurons across the CSPG-rich injured area. These in vitro studies on the CSPG substrates are used to elucidate the mechanisms through which HB-GAM in the extracellular medium reverses the CSPG effect from inhibition to activation of regrowth. Furthermore, the in vitro studies are used to search for molecules that mimick HB-GAM in their binding characteristics and effects on neurite regrowth (HB-GAM mimetics).
HB-GAM and the HB-GAM mimetics that have been selected in the in vitro assays are tested in vivo using the hemisection and hemicontusion SCI models on the cervical area in mice. The effects on recovery are evaluated by behavioral and immunohistochemical assays.
Expected results: Our studies will pave the way for novel treatment strategies of SCI.
Potential application: The current project aims at selecting the drug lead for the clinical Trial.