Molecular basis of pyrethroid resistance

拟除虫菊酯抗性的分子基础

• 批准号: 6689617
• 负责人: KE DONG
• 金额: $ 22.43万
• 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/6689617
• 关键词: Molecular; basis; pyrethroid; resistance

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）：这项研究的长期目标是了解昆虫中杀虫剂耐药性的分子基础。作为人类病原体的携带者，虫害（例如蟑螂和蚊子）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。大量使用拟除虫菊酯杀虫剂来控制这些害虫，导致耐药的害虫群体迅速选择。阻力的发展构成了有效控制害虫的主要障碍。钠通道蛋白（拟除虫菊酯的靶标）中的突变是拟除虫菊酯耐药性的主要原因，导致所有拟除虫菊酯杀虫剂的耐耐药性。对天然发生的拟除虫菊酯抗性相关的钠通道突变和替代切换变体的分析表明，钠通道反膜螺旋螺旋4（S4）和6（S6）在拟甲虫素耐药中的关键作用。但是，这些突变如何赋予拟除虫菊酯抗性。在这项研究中要研究的中心工作假设是，拟除虫菊酯抗性突变会影响S6中的拟除虫菊酯与推定位点的结合，并且/或促进S4/S6在通道失活期间向静止状态的运动，这受到甲状腺动物的抑制。通过分析天然和实验室创建的突变，将使用分子遗传，电生理和药理方法的结合来理解机械水平上的拟除虫菊酯作用/抗性。具体目的是：1。检查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。拟除虫菊酯耐药突变对蟑螂钠通道门控动力学的影响。 3。对第四和第六跨膜段在拟除虫菊酯耐药中的作用的全面检查。