A Genome-Wide Analysis of Nociception Molecules, from Expression to Function

从表达到功能的伤害感受分子的全基因组分析

• 批准号: 8193736
• 负责人: William D Tracey
• 金额: $ 29.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193736
• 关键词: Acute; Acute Pain; Afferent Neurons; Analgesics; Behavior; Candidate Disease Gene; Cells; Development; Drosophila genus; Drosophila melanogaster; Epitopes; Gene Expression Profile; Genes; Genetic; Genetic Screening; Homologous Gene; Human; Hyperalgesia; Label; Larva; Lasers; Lead; Longitudinal Studies; Mechanics; Mediating; Microscopy; Molecular; Mutation; Names; Neuraxis; Neurons; Nociception; Nociceptors; Output; Pain; Painless; Pathway interactions; Pattern; Phenotype; Proteins; RNA; RNA Interference; Reporter; Research; Sampling; Sensory; Signal Transduction; Signaling Molecule; Syndrome; Testing; Thermal Hyperalgesias; Tissues; Transgenic Organisms; Tumor Necrosis Factor-alpha; Yeasts; allodynia; fly; genome-wide; genome-wide analysis; human TNF protein; in vivo; insight; mutant; novel; transcription factor

DESCRIPTION (provided by applicant): A thorough understanding of the molecular machinery that operates in nociceptive sensory neurons will lead to greater understanding of the protective molecular mechanisms of acute pain. To identify nociception molecules, we previously carried out a genetic screen for nociception defective mutants using the fruitfly Drosophila melanogaster. This led to our discovery of the painless gene, which shows enriched expression in nociceptive sensory neurons and is required for acute nociception. The painless gene, as well as a related gene named dTRPA1, encode homologues of TRPA1. Human mutations in TRPA1 mutations lead to familial episodic pain syndrome (FEPS) and TRPA1 is highly expressed in nociceptor neurons. We have identified pickpocket as a critical regulator of mechanical nociception which is specifically expressed in Drosophila nociceptors. The purpose of this proposal is to identify other genes expressed in nociceptor neurons of Drosophila and to test the functional requirement of those genes in nociception. Building upon our recent studies that identified the Class IV multidendritic neurons as polymodal nociceptors of the Drosophila larva we will: 1) Determine the complete transcriptome of nociceptive Class IV multidendritic neurons. 2) Test the functional requirement of genes with enriched expression in nociceptive sensory neurons using tissue specific RNAi knockdown in these cells in vivo. 3.) Functionally characterize a subset of novel genes that we identify to be essential for nociception in Aims 1 and 2. In the short term, these studies will provide critical insight into molecular and cellular mechanisms of nociception using a high throughput approach that is made possible using Drosophila. In the long term, these studies may eventually allow for the identification of evolutionarily conserved mechanisms that contribute to human nociception. ! PUBLIC HEALTH RELEVANCE: The new nociception signaling molecules that we have and will discover in the proposed studies will have a sustained and profound impact on the field of nociception research.

描述（由申请人提供）：对伤害性感觉神经元中运作的分子机制的透彻理解将导致对急性疼痛的保护性分子机制的更好理解。为了鉴定伤害感受分子，我们先前使用果蝇进行了伤害感受缺陷突变体的遗传筛选。这导致我们发现了无痛基因，该基因在伤害性感觉神经元中表达丰富，并且是急性伤害性感受所需的。无痛基因以及一个名为dTRPA1的相关基因编码TRPA1的同源物。TRPA1突变中的人类突变导致家族性发作性疼痛综合征（FEPS），并且TRPA1在伤害感受器神经元中高度表达。我们已经确定了扒手作为一个关键的调节器的机械伤害，这是专门表达在果蝇伤害感受器。本研究的目的是鉴定果蝇伤害感受器神经元中表达的其他基因，并测试这些基因在伤害感受中的功能需求。基于我们最近的研究，确定IV类多树突神经元作为果蝇幼虫的多模态伤害感受器，我们将：1）确定伤害感受IV类多树突神经元的完整转录组。2)使用组织特异性RNAi在这些细胞中体内敲低，测试在伤害感受性感觉神经元中具有富集表达的基因的功能需求。3.）第三章功能特征的一个子集的新的基因，我们确定是必不可少的伤害感受的目的1和2。在短期内，这些研究将提供关键的洞察伤害感受的分子和细胞机制，使用高通量的方法，这是可能使用果蝇。从长远来看，这些研究可能最终允许识别有助于人类伤害感受的进化保守机制。! 公共卫生相关性：我们已经发现并将在拟议的研究中发现的新的伤害感受信号分子将对伤害感受研究领域产生持续而深远的影响。