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Landis Award for Outstanding Mentorship

兰迪斯杰出指导奖

基本信息

批准号：
10661432
负责人：
Marc R Freeman
金额：
$ 15.4万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-02-28
项目状态：
已结题

项目摘要

Project summary 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-76àCacophonyàCamK-IIàdSarm 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-76àCacophonyàCamK-IIàdSarm 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.

项目概要神经系统损伤可能会对大脑或神经功能产生毁灭性的长期影响，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，仍然不明确。在我们之前的工作中我们试图确定轴突切除后驱动轴突变性所需的分子，并确定 dSarm/Sarm1 是关键驱动轴突自动破坏的信号分子。在 dsarm/Sarm1 无效突变果蝇或小鼠中，切断的远端轴突确实损伤后数周内不会退化并保持形态完整。了解 dSarm/Sarm1 如何发出信号轴突现在是该领域的主要焦点，但绝大多数研究都集中在轴突切除术的最终结果上—— 轴突变性——发生在轴突切除术后数小时至数天。在前期工作中我们发现神经损伤导致切断的轴突和相邻完整轴突的轴突运输发生快速变化（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传播到整个神经以激活这些反应（我们将其称为第一阶段）反应），以及神经元和神经胶质细胞在此过程中发挥的作用。有趣的是，我们发现 dSarm 的组件信号通路、Ca2+驱动的 Unc-76àCacophonyàCamK-IIàdSarm 信号通路以及 MAPK 通路在损伤后 3 小时内发挥重要作用，改变轴突细胞生物学和功能。此外，我们发现神经胶质细胞受体 Draper/MEGF10 在神经胶质细胞中发挥作用，激活完整神经元的第一阶段反应（但不是切断的神经元）在受伤后3小时内。在目标 1 中，我们将描述 dSarm/Sarm1 和轴突的新角色死亡信号机制以简单的方式调节完整神经元和切断的轴突的早期（第一阶段）反应遗传性可治疗的神经损伤，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-76àCacophonyàCamK-IIàdSarm 信号通路和 MAPK 的新作用对神经损伤的轴突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 信号通路如何帮助沿着神经传播损伤信号调节轴突生理学的神经范围变化。这项工作将为轴突死亡如何提供重要的新见解信号分子调节对神经损伤的急性反应，识别参与损伤信号传导的新分子（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结果 Draper/MEGF10 在神经损伤反应的急性窗口期发挥新作用。鉴于 dSarm/Sarm1 和 Draper/MEGF10 信号通路（及其功能作用）高度保守，我们的工作将阐明神经系统损伤信号传导的基本机制应与人类神经损伤高度相关神经系统疾病。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Astrocytes close a motor circuit critical period.

DOI：
10.1038/s41586-021-03441-2
发表时间：
2021-04
期刊：
Nature
影响因子：
64.8
作者：
通讯作者：

Signaling mechanisms regulating Wallerian degeneration.

DOI：
10.1016/j.conb.2014.05.001
发表时间：
2014-08
期刊：
Current opinion in neurobiology
影响因子：
5.7
作者：
Freeman MR
通讯作者：
Freeman MR

Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia.

DOI：
10.1016/j.neuron.2020.11.012
发表时间：
2021-02-03
期刊：
Neuron
影响因子：
16.2
作者：
Hsu JM;Kang Y;Corty MM;Mathieson D;Peters OM;Freeman MR
通讯作者：
Freeman MR

Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2.

DOI：
10.1016/j.cub.2015.06.045
发表时间：
2015-08-17
期刊：
Current biology : CB
影响因子：
0
作者：
Sreedharan J;Neukomm LJ;Brown RH Jr;Freeman MR
通讯作者：
Freeman MR

Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease.

DOI：
10.1016/j.nbd.2021.105368
发表时间：
2021-07
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Peters OM;Weiss A;Metterville J;Song L;Logan R;Smith GA;Schwarzschild MA;Mueller C;Brown RH;Freeman M
通讯作者：
Freeman M