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: 9009548
• 负责人: William D Tracey
• 金额: $ 7.73万
• 依托单位: TRUSTEES OF INDIANA 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9009548
• 关键词: Genome; Wide; Analysis; Nociception; Molecules

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. !

描述（由申请人提供）：对在伤害感受感官神经元中运行的分子机械的透彻理解将使人们对急性疼痛的保护性分子机制有更多了解。为了鉴定伤害性分子，我们以前使用果蝇果蝇甲那藻剂进行了遗传筛选，以使伤害感受不良突变体。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现出富集的表达，并且是急性伤害感受所必需的。无痛基因以及名为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）和TRPA1在伤害感受器神经元中高度表达。我们已经确定了扒手是机械伤害感受的关键调节剂，该调节剂在果蝇伤害感受器中特别表达。该建议的目的是鉴定果蝇伤害神经元中表达的其他基因，并在伤害感受中测试这些基因的功能需求。在我们最近的研究基础上，将IV类多端神经元确定为果蝇幼虫的多发性伤害感受器，我们将：1）确定IV类多个型多阶层神经元的完全转录组。 2）测试在体内这些细胞中使用组织特异性RNAi敲低的伤害性感觉神经元中具有富集表达的基因的功能需求。 3.）在功能上表征了我们确定在目标1和2中对伤害感受至关重要的新型基因的子集。在短期内，这些研究将使用高吞吐量的方法来对细胞感受的分子和细胞机制进行关键的见解，而高吞吐量使用果蝇使用果蝇。从长远来看，这些研究最终可能允许鉴定有助于人类伤害感受的进化保守机制。呢