Molecular mechanisms of action and resistance of sodium channel-targeting insecti

描述（由申请人提供）：本研究的长期目标是了解拟除虫菊酯类杀虫剂和钠通道阻断剂杀虫剂（SCBIs）两类重要杀虫剂的分子作用和抗性机制。控制引起重大公共卫生关注的节肢动物害虫的战略继续严重依赖使用相对安全的杀虫剂。目前，拟除虫菊酯是杀虫剂处理过的蚊帐（ITNs）中用于控制疟疾的唯一一类杀虫剂，因为它们作用快、效率高、对人类的毒性相对较低。然而，持续使用拟除虫菊酯类杀虫剂的一个主要威胁是抗药性的发展。茚虫威及其活性代谢物（DCJW）是一种新型单效杀虫剂，也符合病媒控制标准，可作为拟除虫菊酯类杀虫剂的替代杀虫剂。拟除虫菊酯和茚虫威均以电压门控钠通道为目标；然而，它们的作用模式在分子水平上还没有被很好地理解，这是表征抗性机制的主要障碍。本次更新的具体目的是：1)拟除虫菊酯类杀虫剂作用和抗性的分子基础的表征；2)茚虫威/DCJW对钠通道的受体位点和分子作用的鉴定。分子、电生理和计算机建模方法的结合将用于测试新的假设，最终目标是确定昆虫钠通道上难以捉摸的拟除虫菊酯和吲哚虫威受体位点的分子特性。从这项基础研究中获得的新知识将对未来有效监测和管理战略的发展产生重大影响，以控制威胁人类健康的主要节肢动物害虫。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular action and resistance mechanisms of two important classes of insecticides, pyrethroids and sodium channel blocker insecticides (SCBIs). Strategies for the control of arthropod pests of major public health concerns continue to rely heavily on the use of relatively safe insecticides. Currently, pyrethroids are the only class of insecticides used in insecticide treated nets (ITNs) for malaria control, due to their fast acting, high efficacy, and relative low toxicity to humans. However, a major threat to the sustained use of pyrethroids is the development of resistance. Indoxacarb and its active metabolite (DCJW), the first member of a new class of SCBIs, also meets vector control criteria, and could be an alternative insecticide to pyrethroids. Both pyrethroids and indoxacarb target voltage-gated sodium channels; however, the modes of their action are not well understood at the molecular level, which presents a major obstacle to the characterization of mechanisms of resistance. The specific aims of this renewal proposal are: 1) Characterization of the molecular basis of pyrethroid action and resistance, and 2) Identification of the receptor site and molecular action of indoxacarb/DCJW on sodium channels. A combination of molecular, electrophysiological, and computer modeling methods will be used to test novel hypotheses, with the final goal of defining the molecular identities of the elusive pyrethroid and indoxacarb receptor sites on the insect sodium channel. New knowledge gained from this fundamental research will have significant impact on future development of effective monitoring and management strategies for controlling major human health-threatening arthropod pests. PUBLIC HEALTH RELEVANCE: This application describes basic research to understand how pyrethroid and indoxacarb insecticides interact with the voltage-gated sodium channel at the molecular level and how insect pests develop resistance to these insecticides. The knowledge gained from this research will have important implications for the development of strategies to control arthropod vectors that transmit important human diseases including malaria.