Molecular Bases of Neuronal Connectivity

描述（由申请人提供）：在正常情况下，成熟的视网膜神经节细胞（RGC）在视神经损伤后不能再生其轴突，并且很快开始死亡。然而，在先前的授权期间显示，如果巨噬细胞在眼中被激活，许多RGC在轴突切断后存活，并通过视神经的抑制环境再生其轴突。巨噬细胞中的一种蛋白质被鉴定为可能介导这些作用。 目的1将研究这种巨噬细胞衍生的蛋白质是否足以刺激体内视神经再生，确定这种蛋白质是否正常存在于发育中的视觉系统中，并确定其受体。目的2将测试的假设，巨噬细胞衍生的蛋白质和某些辅助因素诱导轴突再生所需的不同的分子变化，并调查诱导的一些基因产物的功能意义。这项工作将利用在先前的资助期间所做的研究，其中使用荧光激活细胞分选纯化RGCs，然后进行微阵列分析，以研究与成功轴突再生相关的基因表达程序。目标3将测试的假设，即在前一个资助期分离的嘌呤敏感激酶是一个信号转导通路的一部分，连接生长因子刺激轴突再生所需的基因表达的变化。这项研究将大大增加我们对视神经再生的理解，并可能为青光眼和其他神经系统退行性或创伤性疾病的治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Under normal circumstances, mature retinal ganglion cells (RGCs) cannot regenerate their axons after optic nerve damage and soon begin to die. However, it was shown in the prior grant period that if macrophages become activated in the eye, many RGCs survive axotomy and regenerate their axons through the inhibitory environment of the optic nerve. A protein from macrophages was identified that may mediate these effects. Aim 1 will investigate whether this macrophage-derived protein is sufficient to stimulate optic nerve regeneration in vivo, determine whether this protein is normally present in the developing visual system, and identify its receptor. Aim 2 will test the hypothesis that the macrophage-derived protein and certain ancillary factors induce distinct molecular changes required for axon regeneration, and investigate the functional significance of some of the gene products that are induced. This work will capitalize on studies done in the prior grant period which used fluorescence-activated cell sorting to purify RGCs, followed by microarray analysis, to investigate the program of gene expression associated with successful axon regeneration. Aim 3 will test the hypothesis that a purine-sensitive kinase that was isolated in the prior funding period is part of a signal transduction pathway linking growth factor stimulation to the changes in gene expression required for axon regeneration. This research will add significantly to our understanding of optic nerve regeneration, and may provide novel targets for therapeutic interventions in glaucoma and other degenerative or traumatic disorders of the nervous system.