MOLECULAR BASES OF NEURONAL CONNECTIVITY

描述（改编自申请人摘要）：在正常情况下， 视网膜神经节细胞在损伤后不能再生其轴突。 受损的轴突在损伤部位仅显示出不成功的发芽，并且在损伤后， 几天后，细胞开始死亡。 然而，对透镜的轻微损伤 信号刺激大量神经节细胞在轴突切断后存活， 通过视神经再生轴突，视神经通常被视为 抑制生长。 透镜损伤激活了常驻小胶质细胞， 浸润性巨噬细胞 已知这些细胞对 受损的神经元，有些是有益的，有些是有害的。 具体目标1将 研究大鼠透镜损伤的轴突促进作用是否 通过小胶质细胞、巨噬细胞或其他细胞类型介导， 确定是否可以改变这种反应的特定方面，以增强 神经节细胞存活和轴突生长。 补充研究 目的2将检测透镜是否刺激细胞存活和轴突再生 穿刺可以通过增加细胞内的 第二信使，环AMP，或防止神经胶质瘢痕形成 在病变部位。 在更基本的层面上，目标3和4将调查 控制视网膜神经节细胞轴突生长的分子机制。 对低等脊椎动物的研究表明，AF-1是一种由哺乳动物分泌的小因子， 视神经胶质，诱导视网膜神经节细胞表达一系列的 生长相关基因和延长长轴突。 胶质细胞 哺乳动物周围神经系统高度支持轴突生长， 制备与AF-1相似或相同的低分子量生长因子。 目标3 将研究哺乳动物AF-1在视神经再生中的作用， 高等脊椎动物。 最后，对低等脊椎动物的研究也表明， 导致轴突生长的细胞内步骤包括 嘌呤敏感机制 为了研究该激酶在 控制哺乳动物视网膜神经节细胞轴突生长，Aim 4将 分离激酶，克隆其基因，并探讨其对 通过构建显性失活突变体进行视神经再生， 研究它在控制基因表达中的作用。 这些研究将提供 新的见解，控制轴突生长的基本机制，在初级 视觉通路，增强我们受伤后恢复视觉功能的能力 或青光眼。

DESCRIPTION (adapted from applicant's abstract): Under normal circumstances, retinal ganglion cells are unable to regenerate their axons after injury. Damaged axons show only abortive sprouting at the site of injury, and after a few days, cells begin to die. However, minor injury to the lens produces signals that stimulate numerous ganglion cells to survive axotomy and to regenerate their axons through the optic nerve, a territory generally viewed as being inhibitory to growth. Lens injury activates resident microglia and infilitrative macrophages. These cells are known to exert multiple effects on injured neurons, some beneficial and others destructive. Specific Aim 1 will investigate whether the axon-promoting effects of lens damage in the rat are mediated through microglia, macrophages, or other cell types, and will determine whether specific aspects of this response can be altered to enhance ganglion cell survival and axon growth even further. Complementary studies in Aim 2 will examine if cell survival and axon regeneration stimulated by lens puncture can be augmented by treatments that increase intracellular levels of the second messenger, cyclic AMP, or that prevent the formation of a glial scar at the lesion site. At a more basic level, Aims 3 and 4 will investigate the molecular mechanisms that control axon outgrowth in retinal ganglion cells. Research in lower vertebrates has shown that AF-1, a small factor secreted by optic nerve glia, induces retinal ganglion cells to express a constellation of growth-associated genes and to extend lengthy axons. Glial cells of the mammalian peripheral nervous system are highly supportive to axon growth, and make a low molecular weight growth factor similar or identical to AF-1. Aim 3 will investigate the role of mammalian AF-1 in optic nerve regeneration in higher vertebrates. Finally, studies in lower vertebrates also show that one of the intracellular steps leading to axon outgrowth involves a purine-sensitive mechanism. To investigate the role to this kinase in controlling axon outgrowth in mammalian retinal ganglion cells, Aim 4 will isolate the kinase, clone its gene, and investigate its' significance for optic nerve regeneration by constructing dominant-negative mutants and examining its role in controlling gene expression. These studies will provide new insights into the basic mechanisms that control axon growth in the primary visual pathway, and enhance our ability to restore visual function after injury or in glaucoma.