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.

项目摘要神经系统损伤可能会对大脑或神经功能产生毁灭性的影响，但发出信号途径调节神经系统对损伤的反应，尤其是在早期急性阶段，仍然定义很差。在我们以前的工作中我们感觉到要确定轴突切开术后驱动轴突变性所需的分子，并将DSARM/SARM1识别为钥匙驱动轴突自动毁灭的信号分子。在DSARM/SARM1 NULL突变蝇或小鼠中，严重的远端轴突DO 受伤后几周内不归化，并且在形态上保持完整。了解DSARM/SARM1在轴突现在是该领域的主要重点，但是绝大多数研究都集中在轴突切开术的最终结果上 - 轴突变性 - 发生轴突切开术后数小时至几天。在初步工作中，我们发现神经损伤导致严重轴突和相邻完整的轴突转运的快速变化（在受伤后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。我们希望理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（我们称为第1阶段反应），以及神经元和神经胶质在此过程中扮演的角色。有趣的是，我们发现DSARM的组成部分信号通路，Ca2+驱动的UNC-76àCacophonyàCamk-iiàdSarm信号通路和组件 MAPK途径在受伤后3小时内起重要作用，以改变轴突细胞生物学和功能。另外，我们发现神经胶质接收器draper/megf10在胶质中起作用，以激活完整神经元中的1阶段响应（但不是严重的神经元）在受伤后3小时内。在AIM 1中，我们将表征DSARM/SARM1和AXON的新颖作用在简单，简单的，简单的神经元和严重轴突中调节早期（第1阶段）反应中的死亡信号机制可基因牵引的损伤神，以及这些信号事件如何改变神经生理学。在AIM 2中，我们将执行类似的研究以探索UNC-76àCacophonyàCamk-iiàdSarm信号通路和MAPK的新作用轴突1中的信号传导对神经损伤的反应。在AIM 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对损伤的反应，以及draper信号通路如何有助于沿着神经传播损伤信号调节轴突生理学的整个神经变化。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，确定与损伤信号传导有关的新分子（UNC-76， cacophony，camk-ii），阐明MAPK信号传导如何驱动受伤后轴突生物学的变化，并描绘出令人兴奋的描述在神经对损伤的急性窗口中，draper/megf10的新角色。鉴于DSARM/SARM1和 Draper/MEGF10信号通路（及其功能角色）是高度保守的，我们的工作将阐明神经系统损伤信号的基本机制应该与人类神经损伤具有很高的相关性和神经疾病。

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）

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

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：

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

WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering.

DOI：
10.1016/j.cub.2012.02.043
发表时间：
2012-04-10
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Avery, Michelle A;Rooney, Timothy M;Pandya, Jignesh D;Wishart, Thomas M;Gillingwater, Thomas H;Geddes, James W;Sullivan, Patrick G;Freeman, Marc R
通讯作者：
Freeman, Marc R