Receptors and Circuits for DEET Detection and Improving Repellents

用于避蚊胺检测和改进驱虫剂的受体和电路

• 批准号: 9012077
• 负责人: Anandasankar Ray
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012077
• 关键词: Aedes; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Biological Models; Brain; Calcium; Cell Line; Chemicals; Country; Culicidae; Dengue; Dengue Virus; Detection; Development; Disease; Drosophila genus; Drosophila melanogaster; Effectiveness; Enhancers; Female; Foundations; Future; Generations; Genes; Goals; Hand; Health; Housing; Human; Image; Income; Insect Repellents; Insecta; Label; Lead; Ligands; Methods; Molecular; Morbidity - disease rate; Neurons; Olfactory Pathways; Pathway interactions; Plant Roots; Play; Populations at Risk; Prevention; Process; Property; Role; Signal Transduction; Skin; Smell Perception; Source; System; Techniques; Technology; Testing; Vaccines; Validation; Yellow Fever; Yellow fever virus; cheminformatics; comparative; cost; design; disorder control; food flavor; high throughput screening; improved; mortality; neural circuit; neuromechanism; neuronal circuitry; neurophysiology; novel; olfactory receptor; receptor; research study; screening; taste system; vector

 DESCRIPTION (provided by applicant): Insects such as mosquitoes use their olfactory and gustatory systems to find their hosts and in the process can transmit deadly diseases to hundreds of millions of people worldwide causing substantial mortality and morbidity. The chemosensory receptors therefore provide excellent targets to design behavior disruption strategies. The insect repellent DEET is effective against a variety of insects including mosquitoes; however it is rarely used by the population at risk in tropical countries due to high costs relative to incomes, and the inconvenience of continuous application on skin. The effectiveness of DEET is due in part to it being detected by aversive receptors in both the olfactory and the gustatory system; however nothing was known about their identity. In a recent breakthrough using the model system Drosophila melanogaster we have identified a DEET-detecting neuron in the antenna that expresses Ir40a and we have shown that both the neuron and the gene are required for avoidance. We have also developed a cheminformatic method to predict new ligands for the DEET receptor that are from natural sources including compounds found in food and flavoring. The goal of this proposal is to identify the conserved DEET-sensing olfactory and gustatory receptors and utilize them as targets to create novel classes of powerful broad-spectrum insect repellents that are safe and affordable. In addition high-throughput assay platforms with the target receptors for DEET will be created, which will serve as a foundation for discovery of even better repellents in the future. For this proposal we plan to use an array of technologies that involve chemical-informatics, neurophysiology, and behavioral analysis. First, we plan to validate the role of the Ir40a/Ir93a/Ir25a in detection of DEET and use them to test the computationally predicted ligands. Second, we plan to identify gustatory receptors that detect DEET as bitter and then test the predicted ligands as bitter aversive compounds. Third, we propose to identify neuronal circuits in the higher brain centers that process the aversive behavior from the olfactory and gustatory system. And fourth, we will test the dual aversive compounds for repellency in Aedes aegypti mosquitoes transmits Dengue and Yellow fever. Successful completion of this proposal will provide safe, affordable and pleasant smelling odorants that are better than DEET in reducing contact between humans and mosquitoes.

 描述（由适用提供）：诸如蚊子之类的昆虫使用其嗅觉和味觉系统来寻找宿主，在此过程中，可以将致命疾病传播到全球数亿人，从而导致大量死亡和发病率。因此，化学感应受体为设计行为破坏策略提供了极好的目标。昆虫复制剂对包括蚊子在内的各种昆虫有效。但是，由于收入相对于收入的高成本以及连续应用对皮肤的影响，因此在热带国家处于危险中的人口很少使用它。 DEET的有效性部分归因于嗅觉和味道系统中的厌恶接收器检测到的效果。但是，对他们的身份一无所知。在最近使用模型系统果蝇的突破中，我们已经确定了表达IR40A的天线中的DEET检测神经元，我们已经表明神经元和基因都需要避免。我们还开发了一种化学物质方法来预测来自天然来源的DEET受体的新配体，包括食物和调味料中的化合物。该提案的目的是确定保守的DEET感应嗅觉和味觉受体，并将其用作目标，以创建新型的强大的广谱绝缘驱虫剂，这些驱虫剂是安全且负担得起的。此外，将创建具有DEET目标受体的高通量测定平台，这将是发现将来甚至更好的驱虫剂的基础。对于此提案，我们计划使用一系列涉及化学信息学，神经生理学和行为分析的技术。首先，我们计划验证IR40A/IR93A/IR25A在检测DEET中的作用，并使用它们来测试计算预测的配体。其次，我们计划确定将DEET检测为苦味的味觉受体，然后将预测的配体作为苦味化合物测试。第三，我们建议在较高的大脑中心中识别神经元回路，以处理嗅觉和味道系统的厌恶行为。第四，我们将测试双重厌恶化合物在埃及埃及蚊子传播登革热和黄热病中的驱逐力。该提案的成功完成将提供安全，负担得起和宜人的气味，这些气味比减少人类与蚊子之间的接触更好。