Genetic approaches to functional remyelination after SCI

描述(申请人提供)：我们最近的工作表明，胶质限制前体细胞(GRP)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。我们将在这些数据的基础上，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。目标1.使用聚焦甚低频？在脱髓鞘损伤和移植D15A-GRPs(A2B5？)后，我们将确定体外证明抑制少突胶质细胞分化的BMP和Notch信号通路的抑制能否增强移植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。目的2.确定CNTF或NRG1I型或III型神经营养因子在体外和体内促进少突胶质细胞的增殖和成熟，是否会促进植入的GRPs的重新髓鞘形成。目的3.使用AIMS 1和AIMS 2中建立的最佳参数和更具临床相关性的挫伤脊髓损伤，我们将询问重新髓鞘化术是否能促进功能恢复。我们假设，髓鞘再生和增强的白质保留都是最佳恢复所必需的，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.