Genetic Analysis of Nociception in Drosophila

果蝇伤害感受的遗传分析

• 批准号: 7766954
• 负责人: William D Tracey
• 金额: $ 33.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7766954
• 关键词: Afferent Neurons; Ankyrin Repeat; Antibodies; Behavior; Behavioral; Cellular Mechanotransduction; Drosophila genus; Drosophila melanogaster; Epidermis; Family; Fever; Genes; Genetic; In Situ Hybridization; In Vitro; Ion Channel; Larva; Length; Link; Logic; Maps; Mechanics; Mediating; Methods; Modality; Modeling; Molecular; Names; Neurites; Neurons; Nociception; Pain; Painless; Pathway interactions; Pattern; Positioning Attribute; Protein Isoforms; Proteins; Reporter; Research Personnel; Resistance; Resolution; Sensory Thresholds; Signal Pathway; Staining method; Stains; Stimulus; TRP channel; TRPA channel; Temperature; Testing; Therapeutic Intervention; Transgenic Animals; domain mapping; fly; genetic analysis; in vivo; insight; member; mutant; novel; receptor; research study; response; somatosensory; thermal stress

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寻找缓解疼痛的新方法至关重要。为了发现新的伤害感受途径，我们采用了一种使用果蝇的正向遗传方法。利用幼虫对伤害性刺激的行为反应，我们已经确定了无痛基因的突变体，这些突变体在机械和热伤害感受方面有缺陷。无痛在多树突神经元中表达，其在形态上类似于在表皮下具有多分支裸露神经突的脊椎动物伤害感受神经元。无痛蛋白是离子通道的瞬时受体电位家族的成员，其中许多与温度转导和机械转导有关。在果蝇中，三种TRPA通道被认为是热传感器;无痛通道，我们在遗传上鉴定为热伤害感受所需的;果蝇TRPA 1（dTRPA 1）通道，其与趋热性有关;第三种通道，称为发热，提供对热应激的抵抗。虽然TRP通道可以在温度和机械信号转导中发挥作用，但这些通道介导温度和机械刺激反应的分子机制仍然是一个谜。我们的理想定位是使用体内遗传学来理解TRP通道在机械转导和热转导中的基本原理。我们将测试三个假设：1）果蝇TRPA通道组合地决定果蝇幼虫的热伤害感受阈值; 2）果蝇多树突感觉神经元的特定亚类在伤害感受中起作用;以及3）无痛通道的锚蛋白重复结构域对于机械转导是必需的。这些研究将提供深入了解伤害感受的分子和细胞机制，这将有助于开发用于治疗疼痛的治疗干预措施。