Receptors and Circuits for DEET Detection and Improving Repellents

 描述(申请人提供)：蚊子等昆虫利用它们的嗅觉和味觉系统寻找寄主，在这个过程中，可以将致命的疾病传播给全球数亿人，导致大量死亡和发病。因此，化学感觉受体为设计行为干扰策略提供了极好的靶点。驱蚊剂DEET对包括蚊子在内的各种昆虫都有效，但热带国家的危险人群很少使用它，因为相对于收入来说，它的成本很高，而且不方便继续在皮肤上使用。DEET的有效性在一定程度上是因为它被嗅觉和味觉系统中的厌恶受体检测到；然而，人们对它们的身份一无所知。在最近的一项突破性进展中，我们利用模型系统黑腹果蝇，在天线中发现了一个表达Ir40a的DEET检测神经元，并表明该神经元和该基因都是避免使用DEET所必需的。我们还开发了一种化学信息学方法来预测DEET受体的新配体，这些配体来自自然来源，包括在食品和调味品中发现的化合物。这项提议的目标是识别保守的DEET感受器和味觉受体，并利用它们作为靶标来创造安全和负担得起的新型高效广谱驱虫剂。此外，还将创建具有DEET目标受体的高通量分析平台，这将为未来发现更好的驱避剂奠定基础。对于这项提议，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DEET检测中的作用，并用它们来测试计算预测的配体。其次，我们计划识别将DEET检测为苦味的味觉受体，然后将预测的配体测试为苦味厌恶化合物。第三，我们建议识别高级大脑中枢中处理来自嗅觉和味觉系统的厌恶行为的神经元回路。第四，我们将测试双重厌恶化合物在传播登革热和黄热病的埃及伊蚊中的驱避性。这项提议的成功完成将提供安全、负担得起和令人愉快的气味气味，在减少人与蚊子接触方面比DEET更好。

 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.