Molecular basis of pyrethroid resistance

拟除虫菊酯抗性的分子基础

• 批准号: 6572540
• 负责人: KE DONG
• 金额: $ 22.39万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572540
• 关键词: Xenopus; aminoacid; binding sites; chemical binding; chemical kinetics; cockroach; electrophysiology; gene mutation; insecticide biological effect; insecticide resistance; intermolecular interaction; membrane activity; molecular genetics; molecular site; neurotoxins; nucleic acid sequence; pest control; pesticide interaction; pyrethroid; site directed mutagenesis; sodium channel; stereochemistry; voltage /patch clamp

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.

描述（由申请人提供）：本研究的长期目标是了解昆虫对杀虫剂抗性的分子基础。蟑螂、蚊子等害虫作为人类病原体的携带者，是人类健康的主要威胁。此外，蟑螂是室内过敏原的主要来源，也是急性哮喘的病因。大量使用拟除虫菊酯杀虫剂来控制这些害虫导致了抗性害虫种群的快速选择。抗性的产生是有效防治害虫的主要障碍。拟除虫菊酯的靶标钠通道蛋白的突变是拟除虫菊酯耐药性的主要原因，导致对所有拟除虫菊酯杀虫剂产生交叉耐药性。对天然存在的拟除虫菊酯抗性相关的钠通道突变和可变剪接变异的分析表明，钠通道跨膜螺旋 4 (S4) 和 6 (S6) 在拟除虫菊酯抗性中发挥着关键作用。然而，这些突变如何赋予拟除虫菊酯抗性尚不清楚。本研究要检验的核心工作假设是，拟除虫菊酯抗性突变要么影响拟除虫菊酯与 S6 中假定位点的结合，和/或在通道失活期间促进 S4/S6 移动到静息状态，而通道失活被拟除虫菊酯抑制。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，从机械层面了解拟除虫菊酯的作用/耐药性。具体目标是： 1．研究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影响的表征。 3.综合考察第4和第6跨膜片段在拟除虫菊酯抗性中的作用。