TRPA1: a polymodal sensor for aversive stimuli

TRPA1：用于厌恶刺激的多模态传感器

• 批准号: 8294132
• 负责人: CRAIG MONTELL
• 金额: $ 32.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-05 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294132
• 关键词: Acute; Address; Adult; Animal Model; Animals; Anopheles gambiae; Aversive Stimulus; Behavior; Behavioral; Behavioral Mechanisms; Biochemistry; Camphor; Cations; Cell Surface Proteins; Cellular biology; Chemicals; Chemotaxis; Circadian Rhythms; Cues; Culicidae; Detection; Disease; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Event; Exposure to; Eye; Family; Future; G-Protein-Coupled Receptors; Generations; Goals; Heating; Human; Inflammation; Insect Control; Insect Repellents; Insecta; Larva; Lead; Leukocytes; Light; Link; Malaria; Mammalian Cell; Mediating; Melanins; Melanosomes; Modeling; Molecular; Molecular Genetics; Molecular Target; Motor Activity; Neurons; Opsin; Organ; Painless; Pathway interactions; Pest Control; Phospholipase C; Photoreceptors; Production; Reactive Oxygen Species; Research; Rhodopsin; Sensory; Signal Transduction; Simulate; Site; Stimulus; TRPA channel; Temperature; Testing; The Sun; Visual; Work; avoidance behavior; base; behavior influence; citronellal; detector; fly; geraniol; high throughput screening; improved; insight; interdisciplinary approach; light intensity; melanocyte; member; novel; receptor; research study; response; sensor; sperm cell; vector mosquito; warm temperature

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to use the fruit fly, Drosophila melanogaster, as an animal model to unravel the mechanisms through which insects respond to sensory cues, ranging from changes in temperature to insect repellents. These questions are of potential relevance to the control of insect pests, since mosquitoes that spread diseases are attracted to humans through thermosensory, visual and chemical cues. Aversive temperatures and chemical repellents deter insects. Therefore, understanding the mechanisms underlying avoidance behavior may provide important insights into insect pest control. A key group of receptor proteins that sense environmental stimuli are Transient Receptor Potential (TRP) cation channels. Among the 13 Drosophila members, TRPA1 is of particular note as it is a detector for a wide array of noxious sensory inputs, including slightly warm or hot temperatures, insect repellents, and excessive light. Here, we propose to dissect the molecular, cellular and behavioral mechanisms through which TRPA1 allows larvae and adult flies to elude aversive stimuli. To accomplish our goals, we propose to employ a multidisciplinary approach, using a combination of molecular genetics, biochemistry, cell biology, electrophysiology and behavioral approaches. Aim 1 will test the hypothesis that bright light, which larvae avoid, activates TRPA1 through a novel mechanism of light detection that is independent of a cell surface protein. In Aim 2 we propose to test the hypothesis that TRPA1 functions as a detector that allow flies to use the daily changes in temperature to set circadian cycles of locomotor activity. The experiments proposed in Aim 3 will test hypotheses concerning the function and mechanism by which TRPA1 is activated via a thermosensory signaling cascade. This cascade represents a new mode of activation of TRP channels in contrast to the well-known direct activation of "thermoTRPs" by changes in temperature. Aim 4 is an outgrowth of the observation that TRPA1 is required for flies to avoid the insect repellent, citronellal, and this response occurs through both direct and indirect mechanisms in both mosquitoes and fruit flies. In the first part of this aim we will test the hypothesis that an additional TRPA channel functions in the aversive responses to other insect repellents (geraniol and camphor). The second part of aim 4 tests the hypothesis that G-protein coupled receptors detect repellents directly, and initiate signaling cascades that lead to indirect activation of TRP channels. The proposed studies ultimately could lead to the identification of a new generation of safer and more effective repellents to control insect-borne disease by identifying and characterizing molecular targets for such compounds. PUBLIC HEALTH RELEVANCE: Insect pests that spread disease identify their human hosts, and avoid noxious environmental conditions through their ability to detect thermal, chemical and visual cues. The focus of the proposed work is to exploit the great technical advantages of the fruit fly as an animal model to discover molecules and mechanisms that insects use to sense environmental stimuli, with the long-term goal of using these insights to develop new strategies to control the spread of insect-borne disease.

描述（由申请人提供）：拟议研究的长期目标是使用果蝇（Drosophila melanogaster）作为动物模型来揭示昆虫对感官信号（从温度变化到驱虫剂）的反应机制。这些问题与害虫的控制具有潜在的相关性，因为传播疾病的蚊子通过热感、视觉和化学线索被人类吸引。令人厌恶的温度和化学驱虫剂可以阻止昆虫。因此，了解回避行为的机制可能为害虫控制提供重要的见解。感知环境刺激的一组关键受体蛋白是瞬时受体电位 (TRP) 阳离子通道。在果蝇的 13 个成员中，TRPA1 特别值得注意，因为它是多种有害感官输入的探测器，包括微温或高温、驱虫剂和过度光照。在这里，我们建议剖析 TRPA1 使幼虫和成蝇逃避厌恶刺激的分子、细胞和行为机制。为了实现我们的目标，我们建议采用多学科方法，结合分子遗传学、生物化学、细胞生物学、电生理学和行为方法。目标 1 将检验这样的假设：幼虫避免的强光通过一种独立于细胞表面蛋白的新型光检测机制激活 TRPA1。在目标 2 中，我们建议测试 TRPA1 作为探测器的假设，允许果蝇利用每日温度变化来设置运动活动的昼夜节律周期。目标 3 中提出的实验将测试有关 TRPA1 通过热感信号级联激活的功能和机制的假设。与众所周知的通过温度变化直接激活“thermoTRP”相比，这种级联代表了 TRP 通道激活的新模式。目标 4 是观察结果的结果，即苍蝇需要 TRPA1 来躲避驱虫剂香茅醛，这种反应通过直接和间接机制在蚊子和果蝇中发生。在该目标的第一部分中，我们将测试以下假设：额外的 TRPA 通道在对其他驱虫剂（香叶醇和樟脑）的厌恶反应中发挥作用。目标 4 的第二部分检验以下假设：G 蛋白偶联受体直接检测驱虫剂，并启动信号级联，从而间接激活 TRP 通道。拟议的研究最终可能导致识别新一代更安全、更有效的驱虫剂，通过识别和表征此类化合物的分子靶标来控制昆虫传播的疾病。 公共卫生相关性：传播疾病的害虫可以识别人类宿主，并通过检测热、化学和视觉线索的能力来避免有害的环境条件。拟议工作的重点是利用果蝇作为动物模型的巨大技术优势来发现昆虫用来感知环境刺激的分子和机制，长期目标是利用这些见解来开发控制虫媒疾病传播的新策略。