Cellular and Molecular Mechanisms Underlying Neuronal Type-specific Axon Regeneration

神经元类型特异性轴突再生的细胞和分子机制

基本信息

批准号：
10587352
负责人：
Yang Xiang
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-06 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587352
关键词：
5&apos -Nucleotidase ATP Receptors Adenosine Afferent Neurons Anatomy Axon Axotomy Cell Communication Cells Coupled Cues Data Drosophila genus Engineering Environment Environmental Risk Factor Event Exhibits Exocytosis Failure Family Genetic Genetic Models Goals Growth Injury Investigation Label Larva Lesion Mammals Measures Membrane Proteins Metabolic Metabolism Modeling Molecular Natural regeneration Nervous System Nervous System Trauma Neuroglia Neuronal Injury Neurons Nociception Nucleotidases Pilot Projects Process Purinergic P1 Receptors RNA Interference Recovery of Function Resolution Role Signal Transduction Source Specific qualifier value Testing Therapeutic Tissues Touch sensation axon injury axon regeneration design extracellular in vivo in vivo Model injury and repair interdisciplinary approach model organism mutant neuronal excitability neurotransmission novel programs public health relevance real-time images receptor receptor expression regenerative response response to injury sensor spatiotemporal tool

项目摘要

Project description Failure in axon regeneration after nervous system lesion is a major roadblock for functional recovery. Axon regeneration is controlled by both intrinsic and extrinsic cues from both neurons and surrounding glial environment. However, our understanding of glial control of axon regeneration remains incomplete. Here, we investigate axon regeneration of well-defined sensory neurons in Drosophila larvae. This in vivo model offers a powerful opportunity to investigate axon regeneration with single-cell resolution and genetic tractability. Our pilot study has made novel findings by discovering a critical involvement of glia-neuron interactions, in the form of gliotransmission, in specifying axon regenerative differences of neuron types. Based on these findings, we hypothesize that gliotransmission orchestrates neuron type-specific axon regeneration. Specifically, we propose that axotomy activates Ca2+ signals in glial cells to elicit gliotransmission, leading to accumulation of extracellular ATP. ATP is then converted by ecto-5’- nucleotidases to adenosine before activating adenosine receptors in the select neuron type, resulting in neuron type-specific Ca2+ signals and axon regeneration. In this project, we will leverage the power of Drosophila genetics and combine it with multidisciplinary approaches to test this hypothesis. Because axon regeneration mechanisms are conserved, our findings will likely be relevant to other species including mammals.

项目描述神经系统损伤后轴突再生失败是神经系统损伤的主要障碍轴突再生受内在和外在信号控制。然而，我们对神经元和周围神经胶质环境的理解。神经胶质对轴突再生的控制仍然不完整。在这里，我们研究轴突。果蝇幼虫中明确的感觉神经元的再生。提供了一个利用单细胞分辨率研究轴突再生的强大机会我们的试点研究通过发现一个关键点取得了新的发现。神经胶质细胞-神经元相互作用的参与，以神经胶质细胞传递的形式，在指定基于这些发现，我们发现神经元类型的轴突再生差异。具体来说，神经胶质细胞传输协调神经元类型特异性轴突再生。我们建议轴切术激活神经胶质细胞中的 Ca2+ 信号以引发神经胶质细胞传递，导致细胞外 ATP 的积累，然后被 ecto-5'- 转化。在激活选定神经元中的腺苷受体之前，核苷酸酶转化为腺苷类型，产生神经元类型特异性 Ca2+ 信号和轴突再生。我们将利用果蝇遗传学的力量并将其与多学科相结合因为轴突再生机制是检验这一假设的方法。如果保守的话，我们的发现可能与包括哺乳动物在内的其他物种相关。