Cytoskeletal dynamics in axon regeneration

 描述(申请人提供)：这个项目的总体目标是使用遗传易驯化的模式生物秀丽线虫来剖析损伤后轴突再生的分子基础。线虫的小尺寸、透明的身体和简单的解剖结构允许在体内切断单个轴突，并深入研究它们的再生。在之前的资助期间，我们在线虫中使用了大规模的基因筛选来发现在体内发挥促进或抑制再生长作用的保守基因和途径。这些途径中的许多都不同于那些参与发育轴突生长的途径。我们的大规模筛选和对遗传交互作用的分析已经导致了这些再生因子的功能模型，我们将在这个提案中进行机械测试。我们将剖析通过轴突微管动力学抑制轴突再生的信号通路。我们将研究膜转运调节因子在轴突延伸中的作用。这项工作的结果将阐明允许成熟轴突在损伤后重新生长的内在机制。在脊椎动物中，周围神经能够再生，但周围神经损伤后的恢复通常是缓慢和不完整的。哺乳动物中枢神经系统在损伤后经历最小的再生，反映了抑制环境和降低的内在再生能力的综合影响。对再生机制的更好的了解也将有助于我们理解为什么中枢神经系统神经元不能再生。我们的工作解决了促进或抑制轴突再生的内在机制，这是该领域的一个高度优先事项。许多信号通路在轴突再生中具有保守的作用，这表明对线虫轴突再生的分析对于理解医学上相关情况下的轴突修复机制具有重要意义。

 DESCRIPTION (provided by applicant): The overall goal of this project is to use the genetically tractable model organism C. elegans to dissect the molecular basis of axon regeneration after injury. The small size, transparent body, and simple anatomy of C. elegans allows single axons to be severed in vivo and their regrowth studied in depth. In the prior funding period we used large- scale genetic screens in C. elegans to discover conserved genes and pathways that play regrowth-promoting or regrowth-inhibiting roles in vivo. Many of these pathways are distinct from those involved in developmental axon outgrowth. Our large scale screens and analyses of genetic interactions have led to models for the function of these regrowth factors that we will test mechanistically in this proposal. We will dissect a signaling pathway that inhibits axon regrowth via axonal microtubule dynamics. We will investigate the role of membrane trafficking regulators in axon extension. Results from this work will elucidate intrinsic mechanisms that allow mature axons to regrow after damage. In vertebrates, peripheral nerves are capable of regrowth, yet recovery after peripheral nerve trauma is often slow and incomplete. The mammalian 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 will also inform our understanding of why CNS neurons do not regrow. Our work addresses intrinsic mechanisms that promote or inhibit axon regrowth, a high priority for this field. Many signaling pathways have conserved roles in axon regrowth, suggesting analysis of C. elegans axon regrowth has implications for understanding axon repair mechanisms in medically relevant situations.