Cytoskeletal dynamics in axon regeneration

 描述（由申请人提供）：本项目的总体目标是使用遗传学上易于处理的模式生物C。elegans来剖析损伤后轴突再生的分子基础。C.虫体小、透明、解剖结构简单。elegans允许在体内切断单个轴突，并深入研究它们的再生。在前一个资助期，我们在C中使用了大规模的遗传筛查. elegans发现保守的基因和途径，在体内发挥再生促进或再生抑制作用。这些通路中的许多与参与发育轴突生长的通路不同。我们对遗传相互作用的大规模筛选和分析导致了这些再生因子功能的模型，我们将在本提案中对这些模型进行机械测试。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。我们将研究轴突延伸中膜运输调节剂的作用。这项工作的结果将阐明允许成熟轴突在损伤后再生的内在机制。在脊椎动物中，周围神经能够再生，但周围神经创伤后的恢复通常缓慢且不完全。哺乳动物CNS在损伤后经历最小的再生，反映了抑制性环境和降低的内在再生能力的组合效应。对再生机制的进一步了解也将有助于我们理解为什么CNS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，提示C。elegans轴突再生对于理解医学相关情况下的轴突修复机制具有意义。

 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.