Cellular Dynamics of Axon Regeneration

这项工作的目标是确定轴突如何在损伤后再生和重新连接， 作用于单个轴突内的分子调节器。我们的模型系统很简单 动物C。elegans，其中单个轴突可以被切断并在体内再生， 一般环境宽松。我们使用了大规模的基因筛选， 发现促进或抑制轴突再生的保守基因，其中大多数不是 参与了轴突的生长发育我们建议深入研究 以及筛选出的三条新的再生抑制途径的相互作用。 首先，我们将剖析轴突发芽的保守调节因子的作用， 调节神经元脂质代谢。其次，我们将研究一个高度保守的 激酶途径抑制轴突再生。最后，我们将阐明mRNA衰变的作用， 调节轴突再生及其与线粒体功能的潜在联系。结果 从这项工作将阐明内在机制，使成熟的轴突作出反应， 损伤和损伤后再生。在脊椎动物中，外周神经能够 周围神经损伤后的恢复通常缓慢且不完全。的 人CNS在损伤后经历最小的再生，反映了组合效应 抑制性环境和降低的内在再生能力。改进 了解具有高内在再生能力的生物体的再生机制 也将帮助我们理解为什么中枢神经系统神经元不能再生。许多C。elegans 已经发现这些通路在轴突再生中具有保守的作用，这表明 C. elegans轴突再生将继续产生的见解， 神经元修复的一般原理。

The goal of this work is to define how axons regrow and reconnect after injury, focusing on molecular regulators acting within individual axons. Our model system is the simple animal C. elegans, in which single axons can be severed and regrow in vivo in a generally permissive environment. We have used large-scale genetic screens to discover conserved genes that promote or repress axon regrowth, most of which are not involved in developmental axon outgrowth. We propose to examine in depth the roles and interactions of three new regrowth-inhibiting pathways revealed from screening. First, we will dissect the roles of a conserved regulator of axonal sprouting that may regulate neuronal lipid metabolism. Second, we will examine how a highly conserved kinase pathway inhibits axon regrowth. Finally, we will elucidate the role of mRNA decay regulators in axonal regrowth and their potential link to mitochondrial function. Results from this work will elucidate intrinsic mechanisms that allow mature axons to respond to injury and regrow after damage. In vertebrates, peripheral nerves are capable of regrowth, yet recovery after peripheral nerve trauma is often slow and incomplete. The human CNS undergoes minimal regeneration after injury, reflecting the combined effects of an inhibitory environment and of reduced intrinsic regrowth capacity. Improved knowledge of regrowth mechanisms in organisms with high intrinsic regrowth capacity will also inform our understanding of why CNS neurons do not regrow. Many C. elegans pathways have been found to have conserved roles in axon regrowth, indicating the mechanisms underlying C. elegans axon regrowth will continue to yield insights into general principles of neuronal repair.