Molecular basis of pyrethroid resistance

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DESCRIPTION (provided by the applicant): The long-term goal of this research is to understand the molecular basis of insecticide resistance in insects. As carriers of human pathogens, insect pests, such as cockroaches and mosquitoes, are major threats to human health. In addition, cockroaches are a major source of indoor allergens and a cause of acute asthma. The intensive use of pyrethroid insecticides to control these pests has led to rapid selection of resistant pest populations. The development of resistance presents a major obstacle to the effective control of insect pests. Mutations in the sodium channel protein, the target of pyrethroids, are a major cause of pyrethroid resistance, resulting in cross-resistance to all pyrethroid insecticides. Analysis of naturally occurring pyrethroid resistance-associated sodium channel mutations and alternative-splicing variants suggests a critical role of sodium channel trans-membrane helixes 4 (S4) and 6 (S6) in pyrethroid resistance. However, how these mutations confer pyrethroid resistance is not understood. The central working hypothesis to be examined in this research is that pyrethroid-resistance mutations either affect pyrethroid binding to a putative site in S6, and/or facilitate the movement of S4/S6 to the resting state during channel deactivation, which is inhibited by pyrethroids. A combination of molecular genetic, electrophysiological and pharmacological approaches will be used to understand pyrethroid action/resistance at the mechanistic level by analyzing both natural and laboratory-created mutations. The specific aims are:1. Examination of the effect of pyrethroid resistance mutations on pyrethroid binding to cockroach sodium channels.2. Characterization of the effect of pyrethroid resistance mutations on cockroach sodium channel gating kinetics. 3. Comprehensive examination of the role of the 4th and 6th trans-membrane segments in pyrethroid resistance.