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，但信号通路 调节神经系统对损伤的反应，特别是在早期急性阶段，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退化所需的分子，并确定DSARM/Sarm1是驱动轴突自动破坏的关键信号分子。在DSARM/Sarm1缺失突变果蝇或小鼠中，被切断的远端轴突在损伤后几周内不会退化，形态上保持完整。了解DSARM/Sarm1在轴突中的信号是目前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后的最终结果-轴突变性-发生在轴突切断后数小时至数天。在前期工作中，我们发现了神经 损伤导致切断的轴突和邻近完整轴突的轴突运输迅速改变(在损伤后2-3小时内)。 神经元，以及整个神经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整个神经中传播以激活这些反应(我们称之为阶段1 反应)，以及神经元和神经胶质细胞在这一过程中所扮演的角色。有趣的是，我们发现DSARM的组件 信号通路，钙离子驱动的UNC-76→Cacophony→CaMK-II→DSARM信号通路以及 MAPK通路在损伤后3h内对改变轴突细胞的生物学和功能起着重要作用。此外，我们 发现胶质受体Draper/MEGF10在胶质细胞中起作用，激活完整神经元的第一相反应(但不是 损伤后3小时内)。在目标1中，我们将描述DSARM/Sarm1和轴突的这一新角色 死亡信号机制在调节早期(第一相)反应中的完整神经元和切断的轴突在一个简单的， 遗传易受损伤的神经，以及这些信号事件如何改变神经生理学。在《目标2》中，我们将表演 探索UNC-76→Cacophony→CaMK-II→DSARM信号通路和MAPK新作用的类似研究 轴突1相对神经损伤反应的信号转导。在目标3中，我们将确定神经损伤的严重程度如何调节 神经元和神经胶质细胞对损伤的反应，以及Draper信号通路如何帮助将损伤信号沿着神经传递到 调节轴突生理的全神经变化。这项工作将为轴突如何死亡提供重要的新见解 信号分子调节神经损伤的急性反应，识别参与损伤信号传递的新分子(UNC-76， Cacophony，CaMK-II)，阐明MAPK信号如何驱动损伤后轴突生物学的变化，并描绘出令人兴奋的 Draper/MEGF10在神经损伤反应的急性窗口中的新作用。鉴于DSARM/Sarm1和 Draper/MEGF10信号通路(及其功能角色)高度保守，我们的工作将阐明 神经系统损伤信号的基本机制，应与人类神经损伤和神经系统疾病高度相关。

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.