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Characterization of the signaling pathways that produce nociceptor sensitization in Drosophila

果蝇中产生伤害感受器敏化的信号通路的表征

基本信息

批准号：
10046777
负责人：
GEOFFREY GANTER
金额：
$ 42.6万
依托单位：
UNIVERSITY OF NEW ENGLAND
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：
2015-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046777
关键词：
Address Affect Afferent Neurons Affinity Chromatography Analgesics Animals Behavioral Bioinformatics Biological Models Bone Morphogenetic Proteins C-terminal binding protein Cornea Coupled Data Data Set Dose Drosophila genus Emotional Epidemic Exhibits Future Gene Targeting Genes Genetic Genetic Models Genetic Transcription Genome Goals Health Promotion Histologic Human Hypersensitivity Injury Intractable Pain Investigation Knowledge Larva Lead Life Ligands Light Mammals Maps Measures Mediating Messenger RNA Modeling Neurons Nociception Nociceptors Opiate Addiction Opioid Orthologous Gene Pain Pain management Pathologic Pathway interactions Peripheral Pharmaceutical Preparations Phosphorylation Population Process Quality of life RNA RNA Interference Rattus Recovery Ribosomes Rodent Role Signal Pathway Signal Transduction Signaling Protein Stimulus System Testing Therapeutic Time Tissues Transcriptional Regulation Transducers Translating Translations UV induced UV injury Ultraviolet Rays Wit addiction allodynia avoidance behavior chronic pain chronic painful condition drug efficacy economic impact experimental study extracellular fly healing human disease improved injured knock-down neurophysiology new therapeutic target non-opioid analgesic novel pain reduction receptor response response to injury side effect tool transcription factor transcriptome sequencing ultraviolet

项目摘要

Normal pain promotes health by warning us of potential tissue damage, but abnormal pain reduces the quality of life for millions around the world. Pain sensitization after injury also promotes health by reducing re-injury during healing. Some types of abnormal pain, including chronic pain, result from dysregulation of the pain sensitization system. Available treatment for chronic pain is inadequate, in part because the deleterious side effects of our best analgesics, the opioids, are made more hazardous by longer use. Better treatments for abnormal pain are badly needed. We propose to reveal novel targets for pain medications by exploiting the powerful genetic toolkit of the Drosophila model. When the fruit fly larva is injured by a controlled dose of ultraviolet (UV) radiation, the animal exhibits allodynia, a manifestation of nociceptive sensitization. This means that the injured animal will react with a nocifensive avoidance behavior in the form of an unmistakable corkscrew roll, in response to a thermal stimulus that most uninjured animals find innocuous. This injury induced sensitization paradigm has previously been used to demonstrate that the nociceptor neuron requires signaling by the Bone Morphogenetic Proteins (BMP) pathway to produce allodynia. BMP signaling components in the fly are very similar to their mammalian orthologs. Preliminary results indicate that a transcriptional and translational response is necessary in the nociceptor neurons in order to produce allodynia following injury. Aim 1 will examine the necessity of a set of BMP related transcriptional regulators like brinker, yorkie and bantam. This will be accomplished by targeting an RNAi silencing construct of each gene specifically to the nociceptor neurons using the Gal4/UAS system. Aim 2 will bring additional BMP pathway and other components to light by identifying transcriptional and translationally regulated genes, again using Gal4/UAS gene targeting, ribosome-tagging and immunopurification tools, RNA sequencing and bioinformatics. Aim 3 will begin to translate the discoveries made in Drosophila into mammalian systems by testing BMP pathway inhibiting drugs for efficacy in providing relief from injury-induced pain sensitization. The proposed studies have the potential to identify all components regulated by transcription and translation in the signaling pathways required for allodynia. Because of the high degree of functional conservation between fly and mammalian BMPs, components identified by these experiments may represent targets for novel medications for the treatment of abnormal pain in humans.

正常的疼痛通过警告我们潜在的组织损伤来促进健康，但不正常的疼痛会降低质量。为全世界数以百万计的人提供生命的源泉。受伤后的疼痛敏感性也通过减少再次受伤来促进健康在愈合过程中。某些类型的异常疼痛，包括慢性疼痛，是由疼痛调节失调引起的。敏化系统现有的治疗慢性疼痛是不够的，部分原因是有害的一面，我们最好的止痛药-阿片类药物-的作用因长期使用而变得更加危险。更好的治疗异常疼痛是非常需要的。我们建议通过利用这些药物来揭示止痛药的新靶点。果蝇模型的强大遗传工具包。当果蝇幼虫被控制剂量的紫外线（UV）辐射后，动物表现出异常性疼痛，这是伤害性敏感化的一种表现。这这意味着受伤的动物会以一种明显的伤害性回避行为的形式作出反应，螺旋形滚动，对大多数未受伤的动物认为无害的热刺激作出反应。这种损伤诱导敏化范例先前已被用于证明伤害感受器神经元需要通过骨形态发生蛋白（BMP）途径进行信号传导以产生异常性疼痛。BMP信号传导果蝇中的组分与它们的哺乳动物直系同源物非常相似。初步结果显示，转录和翻译反应在伤害感受器神经元中是必需的受伤后。目的1将研究一组BMP相关的转录调节因子如Brinker的必要性，约克和矮脚鸡。这将通过靶向每个基因的RNAi沉默构建体来实现特别是伤害感受器神经元使用Gal 4/UAS系统。Aim 2将带来额外的BMP途径和其他成分的光，通过识别转录和转录调控基因，再次使用 Gal 4/UAS基因靶向、核糖体标记和免疫纯化工具、RNA测序和生物信息学目标3将开始将果蝇的发现转化为哺乳动物系统，测试BMP途径抑制药物在提供减轻损伤诱导的疼痛致敏中的功效。的拟议的研究有可能确定所有的转录和翻译调控的组成部分，异常性疼痛所需的信号通路由于果蝇和果蝇之间的功能高度保守，和哺乳动物BMP，通过这些实验鉴定的组分可能代表新的BMP的靶点。用于治疗人类异常疼痛的药物。