Cellular Dynamics of Axon Regeneration

这项工作的目标是定义轴突在受伤后如何再生和重新连接，专注于 在单个轴突中起作用的分子调节剂。我们的模型系统是简单的 动物线虫，其中单个轴突可以被切断，并在体内再生 大体上是宽松的环境。我们使用了大规模的基因筛查来 发现促进或抑制轴突再生的保守基因，其中大多数不是 参与发育轴突的生长。我们建议深入研究这些角色 筛选揭示了三个新的再生抑制途径之间的相互作用。 首先，我们将剖析一个保守的轴突萌发调节器的作用，它可能 调节神经元脂代谢。第二，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。 轴突再生中的调节因子及其与线粒体功能的潜在联系。结果 通过这项工作将阐明允许成熟轴突对 受伤并在受损后重新生长。在脊椎动物中，周围神经能够 再生，然而周围神经损伤后的恢复通常是缓慢和不完整的。这个 人类中枢神经系统在损伤后经历最小的再生，反映了联合作用 抑制的环境和降低的内在再生能力。改进 对具有高内在再生能力的生物体再生机制的认识 这也将有助于我们理解为什么中枢神经系统神经元不会再生。许多线虫 已发现通路在轴突再生中具有保守的作用，表明 线虫轴突再生的潜在机制将继续产生对 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.