Genetic Analysis of Nociception in Drosophila

果蝇伤害感受的遗传分析

基本信息

批准号：
7258253
负责人：
William D Tracey
金额：
$ 33.76万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2012-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Understanding molecular mechanisms of somatosensory signaling pathways is critical to find new methods of alleviating pain. To discover novel nociception pathways, we have taken a forward genetic approach using the fruitfly Drosophila melanogaster. Using a larval behavioral response to noxious stimuli we have identified mutants in the painless gene that are defective in mechanical and thermal nociception. Painless is expressed in multidendritic neurons which morphologically resemble vertebrate nociceptive neurons having multiply branched naked neurites beneath the epidermis. The Painless protein is a member of the Transient Receptor Potential family of ion channels, many of which have been implicated in temperature transduction and in mechanotransduction. In Drosophila, three TRPA channels have been implicated as thermosensors; the Painless channel, which we identified genetically as required for thermal nociception, the Drosophila TRPA1 (dTRPAl) channel which has been implicated in thermotaxis, and a third channel named Pyrexia that provides resistance to thermal stress. While it is clear that TRP channels can function in thermosensory and mechanical signal transduction, the molecular mechanisms responsible for mediating responses to temperature and mechanical stimuli by these channels are still a mystery. We are ideally positioned to use in vivo genetics to understand the basic principles underlying TRP channel function in mechanotransduction and in thermotransduction. We will test three hypotheses: 1) that Drosophila TRPA channels combinatorially determine the thermal nociception threshold of the Drosophila larva; 2) that a specific subclass of Drosophila multidendritic sensory neuron functions in nociception; and 3) that ankyrin repeat domains of the Painless channel are essential for mechanotransduction. These studies will provide insight into molecular and cellular mechanisms of nociception that will assist in developing therapeutic interventions for the treatment of pain.

描述（由申请人提供）：了解体感信号通路的分子机制对于找到缓解疼痛的新方法至关重要。为了发现新型的伤害感受途径，我们使用果蝇果蝇Melanogaster采用了一种正向遗传方法。使用对有害刺激的幼体行为反应，我们已经鉴定出在机械和热伤害感受中有缺陷的无痛基因中的突变体。无痛的多层神经元中表达，形态学上类似于脊椎动物伤害性神经元，在表皮下方具有多个分支的裸神经突。无痛蛋白是离子通道的瞬时受体电位家族的成员，其中许多蛋白质与温度转导和机械传输有关。在果蝇中，三个TRPA通道被与热传感器有关。我们在遗传上鉴定出的无痛通道是热伤害感受所需的，果蝇TRPA1（DTRPAL）通道已与热门抗体有关，以及一个名为Pyrexia的第三个通道，该通道具有对热应力的抗性。虽然很明显，TRP通道可以在热感应和机械信号转导中起作用，但这些通道负责介导温度和机械刺激反应的分子机制仍然是一个谜。理想情况下，我们可以使用体内遗传学来理解机械传输和热转化中TRP通道函数的基本原理。我们将检验三个假设：1）果蝇TRPA通道合并确定果蝇幼虫的热伤害感受阈值； 2）果蝇多阶梯性感觉神经元的特定亚类在伤害受伤中； 3）无痛通道的Ankyrin重复域对于机械转移至关重要。这些研究将提供对伤害感受的分子和细胞机制的见解，这将有助于开发治疗疼痛治疗的治疗干预措施。