Molecular mechanisms of axon degeneration

神经系统损伤可能对大脑或神经功能产生破坏性的长期影响，但 调节神经系统对损伤的反应，特别是在早期急性期，仍然没有明确的定义。在我们之前的工作中，我们试图确定轴突切断后驱动轴突变性所需的分子，并确定dSarm/Sarm 1是驱动轴突自动破坏的关键信号分子。在dsarm/Sarm 1无效突变的果蝇或小鼠中，切断的远端轴突在损伤后数周内不会退化并保持形态完整。了解dSarm/Sarm 1如何在轴突中发出信号现在是该领域的一个主要焦点，但绝大多数研究都集中在轴突切断术的最终结果-轴突变性-这发生在轴突切断术后数小时至数天。在前期工作中我们发现 损伤导致切断的轴突和邻近的完整轴突中轴突运输的快速变化（在损伤后2-3小时内 神经元，以及整个神经中完整神经元中感觉信号转导的抑制。我们希望了解 损伤信号如何如此迅速地在神经中传播以激活这些反应（我们称之为第一阶段 反应），以及神经元和神经胶质在这一过程中发挥的作用。有趣的是，我们发现dSarm的组成部分 信号通路，Ca 2+驱动的Unc-76→Cacophony→CamK-II→dSarm信号通路，以及 MAPK通路在损伤后3小时内起重要作用，改变轴突细胞的生物学和功能。另外我们 发现神经胶质受体德雷珀/MEGF 10在神经胶质中起作用，激活完整神经元的1期反应（但不是所有神经元的1期反应）。 切断的神经元）在损伤后3小时内。在目标1中，我们将描述dSarm/Sarm 1和轴突的这种新作用。 在一个简单的， 遗传上易处理的受损神经，以及这些信号事件如何改变神经生理学。在目标2中，我们将执行 类似的研究探索Unc-76→Cacophony→CamK-II→dSarm信号通路和MAPK的新作用 轴突对神经损伤的第一阶段反应中的信号传导。在目标3中，我们将确定神经损伤的严重程度如何调节 神经元和神经胶质对损伤的反应，以及德雷珀信号传导途径如何帮助损伤信号沿着神经传播， 调节神经轴突生理学的变化。这项工作将提供重要的新见解，轴突死亡如何 信号传导分子调节对神经损伤的急性反应，鉴定参与损伤信号传导的新分子（Unc-76， Cacophony，CamK-II），阐明了MAPK信号转导如何驱动损伤后轴突生物学的变化，并描绘了兴奋性的神经元细胞凋亡。 德雷珀/MEGF 10在神经损伤反应急性窗期间的新作用。考虑到dSarm/Sarm 1和 德雷珀/MEGF 10信号通路（及其功能作用）是高度保守的，我们的工作将阐明 神经系统损伤信号传导的基本机制应该与人类神经损伤和神经疾病高度相关。

Nervous system injury can have devastating long-term effects on brain or nerve function, yet signaling pathways that regulate nervous system responses to injury, especially in early acute phases, remain poorly defined. In our previous work we sought to identify molecules required to drive axon degeneration after axotomy and identified dSarm/Sarm1 as a key signaling molecule that drives axon auto-destruction. In dsarm/Sarm1 null mutant flies or mice, severed distal axons do not degenerate and remain morphologically intact for weeks after injury. Understanding how dSarm/Sarm1 signals in axons is now a major focus for the field, but the vast majority of studies have focused on the final outcome of axotomy—axonal degeneration—which occurs many hours to days after axotomy. In preliminary work we discovered that nerve injury leads to rapid changes (within 2-3 hrs after injury) in axon transport in both severed axons and adjacent intact neurons, and a suppression of sensory signal transduction in intact neurons throughout the nerve. We wish to understand how injury signals spread throughout the nerve so quickly to activate these response (which we refer to as Phase 1 responses), and the roles that neurons and glia play in this process. Interestingly, we found that components of the dSarm signaling pathway, the Ca2+-driven Unc-76→Cacophony→CamK-II→dSarm signaling pathway, and components of the MAPK pathway play important roles within 3 hrs after injury to alter axonal cell biology and function. In addition, we found that the glial receptor Draper/MEGF10, functions in glia to activate Phase 1 responses in intact neurons (but not severed neurons) within 3 hrs after injury. In Aim 1 we will characterize this novel role for dSarm/Sarm1 and the axon death signaling machinery in regulation of early (Phase 1) responses in intact neurons and severed axons in a simple, genetically-tractable injured nerved, and how these signaling events alter neurophysiology. In Aim 2 we will perform similar studies to explore a novel role for the Unc-76→Cacophony→CamK-II→dSarm signaling pathway and MAPK signaling in axonal Phase 1 responses to nerve injury. In Aim 3 we will determine how nerve injury severity regulates neuronal and glial responses to injury, and how the Draper signaling pathway helps spread injury signals along a nerve to modulate nerve-wide changes in axon physiology. This work will provide important new insights into how axon death signaling molecules regulate acute responses to nerve injury, identify new molecules involved in injury signaling (Unc-76, Cacophony, CamK-II), clarify how MAPK signaling drives changes in axon biology after injury, and delineate exciting new roles for Draper/MEGF10 during the acute window of nerve responses to injury. Given that dSarm/Sarm1 and Draper/MEGF10 signaling pathways (and their functional roles) are highly conserved, our work will illuminate fundamental mechanisms of nervous system injury signaling that should have high relevance to human neural injury and neurological disease.