Peripheral Glial Response to Sensory Nerve Degeneration

周围神经胶质对感觉神经变性的反应

基本信息

批准号：
9058618
负责人：
MARK M VOIGT
金额：
$ 18.94万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9058618
关键词：
Ablation Address Affect Afferent Neurons Axon Behavior Bioinformatics Biological Assay Biological Models C Fiber CRISPR/Cas technology Caliber Candidate Disease Gene Cells Cephalic Cessation of life Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cutaneous Data Data Set Development Disease Embryo Enzymes Excision Face Fertilization Fishes Foundations Future Ganglia Gene Expression Genes Goals Head Health Immune Immune system In Situ Hybridization Individual Inflammation Injury Investigation Knock-out Knowledge Larva Mediating Messenger RNA Metronidazole Modeling Natural regeneration Nerve Nerve Degeneration Nervous system structure Neural Crest Neuroglia Neurons Neuropathy Nitroreductases Pain Peripheral Peripheral Nerves Phagocytosis Play Prodrugs Quality of life Recruitment Activity Role Schwann Cells Sensory Signal Transduction Site System Techniques Testing Time Transcript Transgenes Transgenic Organisms Trigeminal System Validation Vertebrates Work Zebrafish afferent nerve axon injury axonal degeneration cDNA Library chronic neuropathic pain deletion analysis genetic manipulation glossopharyngeal in vivo lateral line neuronal cell body novel strategies offspring peripheral pain relating to nervous system repaired response response to injury selective expression sensory neuropathy tool transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The focus of this project is the peripheral non-myelinating glia that ensheath the majority of sensory axons. Unmyelinated axons are often damaged and/or lost in neuropathies. The non-myelinating glia are thought to play key roles in the repair, degeneration and/or regeneration of the affected nerves. We have chosen to focus on the response to degeneration of sensory axons, one feature common to many neuropathies. To gain a better understanding of the mechanisms involved in the glial response to axonal damage/degeneration, we developed an inducible model of peripheral sensory nerve degeneration in zebrafish. This model permits the conditional and selective ablation of peripheral sensory neurons and their axons. In our initial studies, we have found evidence that upon axon degeneration, peripheral glia are critical to the removal of axonal debris and recruitment of immune cells to sites of the involved nerves. The hypothesis that will be tested in this proposal is that axonal damage and degeneration induces glia to alter their gene expression, resulting in phagocytic behaviors and signaling to the immune system. In this application, we propose two aims: (1) identify genes involved in the response of peripheral glia to sensory neurodegeneration and (2) to validate the candidate genes identified in Aim 1. This will be achieved through transcriptome analysis of control and metronidazole- treated fish. Validation of candidate genes will be performed using qPCR, in situ hybridization and CRISPR/Cas9 mediated deletion analysis. Identification of involved genes will provide an important foundation for future investigations into the mechanisms by which peripheral glia react to death and degeneration of sensory circuits, and can be used as the starting points for directed studies in higher vertebrates, with the eventual goal of developing new directions in clinical efforts to treat this aspect of many debilitating sensory neuropathies.

描述（由适用提供）：该项目的重点是大部分感觉轴突下方的外围非层状神经胶质。无髓轴通常会在神经病中损坏和/或丢失。人们认为非层状神经胶质在受影响神经的修复，变性和/或再生中起关键作用。我们选择专注于对感觉轴突变性的反应，这是许多神经病常见的特征。为了更好地理解与轴突损伤/变性的神经胶质反应相关的机制，我们开发了斑马鱼中外周感觉神经变性的诱导模型。该模型允许外围感觉神经元及其轴突的条件和选择性消融。在我们的最初研究中，我们发现证据表明，在轴突变性后，周围胶质神经胶质对于去除轴突碎屑和将免疫细胞募集到所涉及神经部位至关重要。该提案中将检验的假设是轴突损伤和变性会诱导神经胶质改变其基因表达，从而导致吞噬性行为和对免疫系统的信号。在此应用中，我们提出了两个目的：（1）确定参与周围神经胶质对感觉神经退行性反应的基因，以及（2）验证AIM 1中鉴定的候选基因。这将通过对照组和甲硝酸甲硝酸甲硝酸甲磺酸治疗的鱼类进行转录组分析来实现。候选基因的验证将使用QPCR，原位杂交和CRISPR/CAS9介导的缺失分析进行验证。鉴定相关基因将为将来研究外周胶质神经胶质对死亡和感觉电路变性的反应的机制提供重要的基础，并可以用作高等脊椎动物中有指导性研究的起点，最终是在临床努力中开发新的方向，以治疗许多衰弱的感官神经病的临床努力。