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

描述（由申请人提供）：对伤害感觉神经元的分子机制的透彻理解将有助于对急性疼痛的保护分子机制有更深入的了解。为了鉴定痛觉分子，我们之前使用果蝇果蝇进行了痛觉缺陷突变体的基因筛选。这导致我们发现了无痛基因，该基因在痛觉感觉神经元中表达丰富，是急性痛觉所必需的。无痛基因以及一个名为dTRPA1的相关基因编码TRPA1的同源物。人类TRPA1突变导致家族性阵发性疼痛综合征（FEPS），而TRPA1在伤害感受器神经元中高度表达。我们已经确定扒手是机械性伤害感受的关键调节器，在果蝇的伤害感受器中特异性表达。本研究的目的是鉴定果蝇伤害感受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，我们确定了IV类多树突神经元是果蝇幼虫的多模态伤害感受器，我们将：1)确定伤害感受器IV类多树突神经元的完整转录组。2)在体内利用组织特异性RNAi敲除这些细胞，检测痛觉感觉神经元中表达富集基因的功能需求。3)。功能特征的一个新基因的子集，我们确定是必不可少的伤害感觉在Aims 1和2。在短期内，这些研究将利用果蝇的高通量方法，为伤害感受的分子和细胞机制提供关键的见解。从长远来看，这些研究可能最终允许鉴定进化上保守的机制，有助于人类伤害感觉。！

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. !