Genetic approaches to functional remyelination after SCI

描述（申请人提供）：我们最近的研究表明，将神经胶质限制性前体细胞（GRPs）移植到脱髓鞘或挫伤性脊髓损伤（SCI）中，可以部分恢复电生理传导和后肢运动恢复。我们将以这些数据为基础，确定人类胚胎干细胞（hESC）在植入受损脊髓后恢复功能的潜力。目的1。使用焦点VLF？我们将确定体外实验证明抑制少突胶质细胞分化的BMP和Notch信号通路是否可以增强移植物细胞的再髓鞘形成能力。我们将研究一些基因和分子生物学方法来抑制BMP和Notch信号。目标2。确定CNTF或NRG1 I型或III型（已知在体外和体内可增强少突胶质细胞增殖和成熟的神经营养因子）是否会增强GRPs移植的髓鞘再生。目标3。使用目标1和目标2中建立的最佳参数以及更具临床相关性的挫伤性脊髓损伤，我们将询问髓鞘再生是否可以增强功能恢复。我们假设脱髓鞘和增强白质保留都是最佳恢复所需要的，并将在这些动物中区分这些影响。

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.