Genetic approaches to functional remyelination after SCI

描述（由申请人提供）：我们最近的工作表明，胶质限制性前体细胞（GRP），移植到脱髓鞘或挫伤性脊髓损伤（SCI），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）植入受损脊髓后恢复功能的潜力。目标1.使用聚焦甚低频？脱髓鞘病变和移植D15 A-GRP（A2 B5？），我们将确定在体外证实抑制BMP和Notch信号传导途径抑制少突胶质细胞分化是否可以增强移植细胞的髓鞘再生能力。我们将研究一些抑制BMP和Notch信号传导的遗传和分子生物学方法。目标2.确定是否交付CNTF或NRG 1型I或III，已知的神经营养因子在体外和体内增强少突胶质细胞的增殖和成熟，将增强髓鞘再生嫁接GRP。目标3.使用目标1和2中建立的最佳参数以及临床上更相关的挫伤SCI，我们将询问髓鞘再生是否可以导致增强的功能恢复。我们假设髓鞘再生和增强的白色物质保留都是最佳恢复所需的，并将在这些动物中区分这些效果。

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.