Genetic approaches to functional remyelination after SCI

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DESCRIPTION (provided by applicant): Our recent work shows that glial restricted precursor cells (GRPs), grafted into a demyelinating or contusive spinal cord injury (SCI), partially restore electrophysiological conduction and hindlimb locomotor recovery. We will build on those data and determine the potential of human embryonic stem cells (hESC) to restore function after engraftment into the damaged spinal cord. Aim 1. Using the focal VLF? demyelinating lesion and grafting D15A-GRPs (A2B5???), we will determine whether inhibition of BMP and Notch signaling pathways, demonstrated in vitro to inhibit oligodendrocyte differentiation, can enhance the remyelination capacity of the engrafted cells. We will examine a number of genetic and molecular biological approaches to inhibiting BMP and Notch signaling. Aim 2. Determine whether delivery of CNTF or NRG1 types I or III, neurotrophic factors known to potentiate oligodendrocyte proliferation and maturation in vitro and in vivo, will enhance remyelination by engrafted GRPs. Aim 3. Using optimal parameters established in Aims 1 and 2 and the more clinically relevant contusion SCI, we will ask whether remyelination can result in enhanced recovery of function. We hypothesize that both remyelination and enhanced white matter sparing are needed for optimal recovery and will distinguish between those effects in these animals.