Chemokine Synergy with PDGF Oligodendrocyte Precursors

描述(申请人提供)：髓鞘形成是 脊椎动物中枢神经系统成熟。发育过程中缺乏髓鞘形成或失去髓鞘 成人的髓鞘会导致严重的功能缺陷。中枢神经系统髓鞘生成 通过在适当的数量和适当的时间发育的少突胶质细胞 所有长投射轴突髓鞘形成的位置。的本地控制 发育期或脱髓鞘疾病后的少突胶质细胞发生 不是很清楚。我们最近发现了一种新的监管机制， 似乎在调节少突胶质细胞的发育中起着关键作用 和髓鞘形成。趋化因子Gro-α通过其受体发出信号， CXCR2，调节少突胶质细胞前体细胞的增殖 血小板衍生生长因子(PDGF)，并提供了一个有效的停止信号 少突胶质细胞前体迁移。在此续订申请中，我们将使用 缺乏CXCR2受体或过度表达配体的转基因动物 Gro-α定义Gro-α/CXCR2信号的功能 少突胶质细胞发育和脱髓鞘反应。毫不含糊地 鉴定我们将利用转基因动物的少突胶质细胞系细胞 这些细胞通过表达增强型绿色被特异性地标记 荧光蛋白(EGFP)从PLP启动子上被赶走。我们将1)测试是否 Gro-α/CCR2通路调控少突胶质细胞的发育 通过比较脊髓髓鞘形成的时间和程度 正常和CXCR2缺失动物之间的髓鞘形成；2)鉴定 Gro-APLHA/CXCR2信号转导途径抑制肿瘤细胞的迁移和扩散 少突胶质细胞前体细胞移植EGFP+细胞的实验研究 绿色荧光蛋白标记的环境和直接时间推移迁移分析 3)确定Gro-α/CXCR2信号转导 增强或抑制成年中枢神经系统髓鞘再生的比较 溶血磷脂诱导野生型EAE脱髓鞘或诱导EAE CXCR2-零动物。这些研究将把Gro-α定义为一个重要的 少突胶质细胞发生中的调控分子及其治疗的潜在靶点 髓鞘疾病，如多发性硬化症和失调性疾病 少突胶质瘤等胶质形成

DESCRIPTION (provided by applicant): Myelination is a crucial process in vertebrate CNS maturation. Lack of myelination during development or loss of myelin in the adult leads to severe functional deficits. CNS myelin is produced by oligodendrocytes that develop in appropriate numbers and at appropriate locations to myelinate all long projection axons. The local control of oligodendrogenesis during development or following demyelinating diseases is not well understood. We recently identified a novel regulatory mechanism that appears to play a key role in regulating the development of oligodendrocytes and in myelination. The chemokine GRO-alpha, signaling through its receptor, CXCR2, regulates the proliferation of oligodendrocyte precursors in response to platelet derived growth factor (PDGF) and provides a potent stop-signal for oligodendrocyte precursor migration. In this renewal application we will use transgenic animals that either lack CXCR2 receptors, or overexpress the ligand GRO-alpha to define the function of GRO-alpha/CXCR2 signaling during oligodendrocyte development and in response to demyelination. To unambiguously identify oligodendrocyte lineage cells we will utilize transgenic animals in which these cells are specifically labeled through expression of Enhanced Green Fluorescent Protein (EGFP) driven off the PLP promoter. We will 1) test if the GRO-alpha/CCR2 pathway regulates development of oligodendrocytes and myelination in the spinal cord, by comparing the timing and degree of myelination between normal and CXCR2 null animals; 2) identify if GRO-aplha/CXCR2 signaling inhibits the migration and dispersal of oligodendrocyte precursors by transplanting EGFP+ cells into different environments as well as direct time lapse migration analyses of EGFP-labeled cells in slice preparations; 3) determine whether GRO-alpha/CXCR2 signaling enhances or inhibits remyelination in the adult CNS by comparing recovery from lysolecithin induced demyelination or induction of EAE in wild type and CXCR2-null animals. These studies will define GRO-alpha as an important regulatory molecule in oligodendrogenesis and a potential target for therapy in diseases of myelin, such as Multiple Sclerosis, and disorders of unregulated gliogenesis such as oligodendroglioma