Molecular basis of pyrethroid resistance

超出提供的空间。这项研究的长期目标是了解昆虫抗药性的分子基础。作为人类病原体的携带者，蟑螂和蚊子等害虫是对人类健康的主要威胁。此外，蟑螂是室内过敏原的主要来源，也是急性哮喘的原因之一。大量使用拟除虫菊酯类杀虫剂来控制这些害虫，导致了抗药性害虫种群的快速选择。抗药性的发展是有效控制害虫的主要障碍。拟除虫菊酯的靶标钠通道蛋白的突变是拟除虫菊酯抗药性的主要原因，导致对所有拟除虫菊酯杀虫剂的交叉抗药性。对自然发生的与拟除虫菊酯抗性相关的钠通道突变和选择性剪接变体的分析表明，钠通道跨膜螺旋4(4美元)和6(6美元)在拟除虫菊酯抗性中起着关键作用。然而，这些突变是如何产生拟除虫菊酯抗性的还不清楚。本研究将检验的中心工作假设是，拟除虫菊酯抗性突变要么影响拟除虫菊酯与$6中假定的位点的结合，要么促进$4/$6在通道失活期间进入静止状态，这是被拟除虫菊酯抑制的。将结合分子遗传学、电生理学和药理学方法，通过分析自然和实验室产生的突变，在机制水平上了解拟除虫菊酯的作用/抗性。具体目的是：1.检测拟除虫菊酯抗性突变对拟除虫菊酯与蟑螂钠通道结合的影响。2.拟除虫菊酯抗性突变对蟑螂钠通道门控动力学的影响3.综合研究第4和第6跨膜节段在拟除虫菊酯抗性中的作用。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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 transmembrane helixes 4 ($4) and 6 ($6) 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 pyrethorid binding to a putative site in $6, and/or facilitate the movement of $4/$6 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 transmembrane segments in pyrethroid resistance. PERFORMANCE SITE ========================================Section End===========================================