Genetic approaches to functional remyelination after SCI

SCI 后功能性髓鞘再生的遗传学方法

• 批准号: 8068505
• 负责人: Scott R Whittemore
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068505
• 关键词: Address; Adult; Animals; Axon; Behavioral; Biological; Brain-Derived Neurotrophic Factor; Cells; Chest; Ciliary Neurotrophic Factor; Contusions; Data; Demyelinations; Dominant-Negative Mutation; Engraftment; Environment; Failure; Functional disorder; Gene Deletion; Genetic; Heterozygote; Hindlimb; Impairment; In Vitro; Injury; Intervention; Lentivirus Vector; Lesion; Locomotor Recovery; Magnetism; Measures; Methods; Modeling; Modification; Molecular Genetics; Monitor; Motor Evoked Potentials; Mus; NRG1 gene; Natural regeneration; Neuregulins; Notch Signaling Pathway; Oligodendroglia; Play; Publications; Publishing; Rattus; Recovery; Recovery of Function; Research Personnel; Retroviridae; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Spinal Cord; Spinal cord damage; Spinal cord injury; Stem cells; Work; cell type; clinically relevant; combinatorial; functional restoration; human embryonic stem cell; in vivo; injury prevention; insight; mouse model; myelination; neurotrophic factor; nicastrin protein; notch protein; partial recovery; precursor cell; response; success; treatment strategy; vector; white matter

Our recently work show 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+DLF demyelinating lesion and grafting D15A-GRPs (A2B5+/NG2+/O4-), 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.

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 复苏我们将在这些数据的基础上，确定人类胚胎干细胞（hESC）的潜力， 植入受损脊髓后恢复功能。目标1。使用焦点甚低频+DLF 脱髓鞘病变和移植D15 A-GRP（A2 B5 +/NG 2 +/O 4-），我们将确定是否抑制 BMP和Notch信号通路，在体外被证明可以抑制少突胶质细胞的分化， 增强移植细胞的髓鞘再生能力。我们将研究一些遗传和 抑制BMP和Notch信号传导的分子生物学方法。目标二。确定是否交付 CNTF或NRG 1 I型或III型，已知可增强少突胶质细胞增殖的神经营养因子， 在体外和体内成熟，将通过移植的GRP增强髓鞘再生。目标3.利用最优 在目标1和2中建立的参数以及临床上更相关的挫伤SCI，我们将询问是否 髓鞘再生可导致增强的功能恢复。我们假设髓鞘再生和 需要增强的白色物质保留以实现最佳恢复，并将区分这些影响， 这些动物。