Receptors and Circuits for DEET Detection and Improving Repellents

 描述（由申请人提供）：蚊子等昆虫使用其嗅觉和味觉系统来寻找其宿主，并在此过程中将致命疾病传播给全球数亿人，导致大量死亡和发病。因此，化学感受器提供了很好的目标，设计行为中断策略。驱蚊剂DEET对包括蚊子在内的各种昆虫有效;然而，由于相对于收入而言成本较高，并且连续涂抹在皮肤上不方便，热带国家的风险人群很少使用它。避蚊胺的有效性部分是由于它被嗅觉和味觉系统中的厌恶性受体检测到;然而，对它们的身份一无所知。在最近的一项突破中，使用模型系统果蝇，我们已经确定了一个DEET检测神经元的天线，表达Ir 40 a，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信息学方法来预测DEET受体的新配体，这些配体来自天然来源，包括在食品和调味品中发现的化合物。该提案的目标是确定保守的DEET感测嗅觉和味觉受体，并利用它们作为目标，以创建安全且负担得起的新型强效广谱驱虫剂。此外，还将建立具有DEET靶受体的高通量检测平台，这将为未来发现更好的驱虫剂奠定基础。对于这个提议，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Ir 40 a/Ir 93 a/Ir 25 a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，我们计划确定味觉受体检测避蚊胺作为苦，然后测试预测的配体作为苦味厌恶化合物。第三，我们建议确定高级大脑中心的神经元回路，这些神经元回路处理来自嗅觉和味觉系统的厌恶行为。第四，我们将测试双重厌恶化合物对传播登革热和黄热病的埃及伊蚊的驱避作用。这项提案的成功完成将提供安全、负担得起和气味宜人的气味剂，这些气味剂在减少人与蚊子之间的接触方面优于避蚊胺。

 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.