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

钠通道靶向昆虫的作用和耐药性的分子机制

• 批准号: 8371255
• 负责人: KE DONG
• 金额: $ 35.56万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371255
• 关键词: Address; Aedes; Arthropod Vectors; Arthropods; Basic Science; Bedbugs; Belief; Binding; Binding Sites; Biochemical; Biology; Collection; Computer Simulation; Culicidae; Development; Dictyoptera; Funding; Future; Goals; Health; Human; Hypersensitivity; Insecta; Insecticides; Knowledge; Lead; Local Anesthetics; Malaria; Methods; Modeling; Molecular; Molecular Genetics; Molecular Mechanisms of Action; Monitor; Mosquito Control; Mutation; Neurons; Neurotoxins; Population; Property; Public Health; Relative (related person); Research; Residual state; Resistance; Resistance development; Series; Site; Site-Directed Mutagenesis; Sodium Channel; Sodium Channel Blockers; Staging; Testing; Toxic effect; Validation; base; fundamental research; human disease; indoxacarb; meetings; member; molecular site; neurotoxin receptor; novel; pyrethroid; receptor; resistance mechanism; resistance mutation; response; vector control; voltage

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.

描述（由申请人提供）：本研究的长期目标是了解两类重要杀虫剂：拟除虫菊酯和钠通道阻滞剂杀虫剂（SCBI）的分子作用和耐药机制。控制主要公共卫生问题的节肢动物害虫的策略仍然严重依赖于相对安全的杀虫剂的使用。目前，拟除虫菊酯是用于控制疟疾的杀虫剂处理蚊帐 (ITN) 中唯一使用的杀虫剂，因为其起效快、功效高且对人类的毒性相对较低。然而，拟除虫菊酯持续使用的主要威胁是耐药性的产生。茚虫威及其活性代谢物 (DCJW) 是新型 SCBI 的第一个成员，也符合病媒控制标准，并且可以作为拟除虫菊酯的替代杀虫剂。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尚未得到很好的理解，这给耐药机制的表征带来了主要障碍。该更新提案的具体目标是：1）表征拟除虫菊酯作用和抗性的分子基础，2）鉴定茚虫威/DCJW对钠通道的受体位点和分子作用。将结合分子、电生理学和计算机建模方法来测试新的假设，最终目标是确定昆虫钠通道上难以捉摸的拟除虫菊酯和茚虫威受体位点的分子身份。从这项基础研究中获得的新知识将对未来制定有效的监测和管理策略以控制威胁人类健康的主要节肢动物害虫产生重大影响。 公共健康相关性：本申请描述了了解拟除虫菊酯和茚虫威杀虫剂如何在分子水平上与电压门控钠通道相互作用以及害虫如何对这些杀虫剂产生抗性的基础研究。从这项研究中获得的知识将对制定控制传播包括疟疾在内的重要人类疾病的节肢动物媒介的策略具有重要意义。