ENHANCING NEURAL STEM CELL ACTIVATION TO IMPROVE WHITE MATTER RECOVERY FROM MILD TBI

Axon damage in white matter tracts is a predominant pathology of acceleration-deceleration forces in traumatic brain injury (TBI). Currently, there are no available treatments that target protection or repair of damaged axons. Very recent studies have now demonstrated that, along with axonal damage, white matter tracts exhibit demyelination after open field blast in non-human primates and in rats with TBI from blast, fluid percussion, or controlled cortical impact. Myelin pathology has not been as well characterized across the spectrum of human TBI cases but demyelination has been associated with primary or secondary damage and may contribute to progressive atrophy. As with axon damage, there are no available treatments that target remyelination to improve white matter integrity and reduce dysfunction in TBI patients. Importantly, demyelination can leave axons vulnerable to further damage. Therefore, remyelination may a) recover function of viable demyelinated axons and b) prevent damaged axons from further degeneration to secondary axotomy, which is the pivotal point for conversion to permanent loss of function.Recovery of axons from damaging insults may be promoted both by neuroprotective effects of remyelination as well as by trophic effects of oligodendrocytes. Interventions to improve the efficiency of remyelination require increasing the pool of available oligodendrocyte progenitor (OP) cells and reducing signals that inhibit OP differentiation into myelinating oligodendrocytes. We have shown that removing an inhibitor of OP differentiation, fibroblast growth factor 2 (FGF2), dramatically improves remyelination and reduces axon damage in the corpus callosum of chronically demyelinated mice. However, FGF2 has pleiotrophic effects that limit therapeutic potential. In the context of mild TBI, amplifying the available pool of OP cells has potential for optimizing remyelination to protect axons and recover efficient nerve conduction.Sonic hedgehog (Shh) signaling maintains the stem cell niche and stimulates neural stem (NS) cell proliferation in the adult CNS. Following injury, Shh has been reported to have restorative effects that promote neural cell survival, increase proliferation of NS cells, and enhance differentiation of NS cells into new neuron and glial cell types. Shh induces oligodendrogenesis and proliferation of OP cells after cryogenic cortical injury. The role of Shh signaling in promoting white matter integrity and remyelination has not been directly tested in TBI with traumatic axonal injury (TAI).Hypothesis: Activation of Shh signaling can enhance the regenerative response of endogenous NS and OP cells to promote white matter integrity and functional recovery following TAI.AIM 1: Increase Shh signaling to stimulate NS cell generation of OP cells.AIM 2: Demonstrate Shh signaling contribution to remyelination and axon protection.Each Aim will exploit genetic mouse models for analysis of in vivo neural stem and progenitor cell responses following mild TBI. The proposed studies will use a mouse model of TAI with acceleration-deceleration induced by concussion from an electronically controlled impactor onto the closed skull. The term TAI refers to the limited areas of significant axonal damage that are found in mild to moderate TBI as compared to the widespread or diffuse axonal injury (DAI) of severe TBI. This mouse mTBI model reflects the white matter pathology of human mild to moderate acceleration-deceleration TBI and facilitates reproducible repeat injury.