Molecular mechanism of juvenile hormone action in mosquito reproduction

保幼激素在蚊子繁殖中作用的分子机制

• 批准号: 10579247
• 负责人: JINSONG ZHU
• 金额: $ 4.01万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579247
• 关键词: Adult; Aedes; Affinity; Alternative Splicing; Binding; Biological Assay; Biology; Blood; Calcium; Cell Nucleus; Cell membrane; Cells; Chemicals; Chromatin; Communicable Diseases; Complex; Culicidae; Cultured Cells; DNA Binding; Dengue Fever; Development; Dimensions; ERG gene; Ecdysterone; Effectiveness; Endocrine; Epidermal Growth Factor Receptor; Evolution; Exhibits; Fat Body; Female; Fertility; Funding; Gene Expression; Genes; Genetic Transcription; Genomics; Global Change; Goals; Homologous Gene; Hormone Receptor; Insecticide Resistance; Insecticides; Juvenile Hormones; Knock-out; Knowledge; Light; Malaria; Measures; Mediating; Membrane; Methoprene; Molecular; Mosquito Control; Mosquito-borne infectious disease; Nuclear; Pathway interactions; Pattern; Pesticides; Play; Population; Proteins; RNA Interference; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Repression; Reproduction; Resistance; Role; Signal Pathway; Site; Specificity; Testing; Time; Tissues; Toxic effect; Zika Virus; dimer; disease transmission; ecdysteroid receptor; egg; hormonal signals; improved; knock-down; mosquito reproduction; non-genomic; prevent; promoter; protein aminoacid sequence; pyrethroid; receptor; response; screening; structural determinants; tool; transcription factor; transcriptome sequencing; transcriptomics; transmission process; vector control; vector mosquito

Project Summary Mosquitoes are responsible for the transmission of many infectious diseases such as malaria, dengue fever, and Zika virus. Vector control using insecticides is currently the primary means of preventing the transmission of these diseases. In light of the rapid spread of insecticide resistance in mosquito populations, it is imperative to add new insecticides with different modes of action to the arsenal of mosquito control agents. The juvenile hormone (JH) signaling pathway is an attractive target for the control of mosquito vectors. JH is a key regulator of mosquito development and reproduction. Exposure of adult mosquitoes to pyriproxyfen, a synthetic JH mimic, has shown promise to effectively sterilize female mosquitoes. Our goal of this project is to elucidate the molecular pathways utilized by JH and its mimics to modulate mosquito fecundity. Mosquito egg development is mainly governed by JH and 20-hydroxyecdysone (20E). In the last funding cycle, we demonstrated that the Methoprene-tolerant (MET) protein is an intracellular receptor of JH. Both natural JH and pyriproxyfen binds to Aedes aegypti MET with high affinity. Upon binding of JH, MET forms a dimer with Taiman, a transcriptional factor that is involved in both JH and 20E responses. The MET-Taiman complex directly regulates the expression of JH-controlled genes. Besides the genomic action, we also reported a rapid JH signaling that is initiated from the plasma membrane. The non-genomic action, which relies on receptor tyrosine kinases (RTK), modulates the DNA-binding of the MET-Taiman complex and regulates the alternative splicing of the taiman gene. While the membrane-initiated JH signaling plays critically important roles in mosquito reproduction, the membrane JH receptor and the specific RTK have not yet been identified in mosquitoes. Our recent study demonstrates that a small portion of MET is associated with the plasma membrane in mosquito cells. Furthermore, depletion of MET eradicates the JH-activated increase in intracellular Ca2+, which is part of extranuclear JH signaling. Thus, our results suggest that the membrane- associated MET acts as a membrane JH receptor to mediate the non-genomic action of JH. In this proposed study, we will test the hypothesis that the JH action in mosquitoes is mediated by both membrane-bound and nuclear MET proteins, and that pyriproxyfen uses this JH signaling pathway to inhibit 20E-regulated gene expression. In Aim 1, we will define the roles of membrane MET in the membrane binding of JH and the membrane-initiated JH signaling. In Aim 2, we will investigate how membrane MET mediates the nongenomic action of JH in mosquitoes. In Aim 3, we will elucidate how pyriproxyfen utilizes the JH signaling pathway to suppress the vitellogenic 20E response. This study will add a new dimension to our understanding of the JH signaling pathway that is required for mosquito reproduction. It may also reveal new targets in the JH signaling pathway that can be exploited for pesticide development.

项目摘要 蚊子负责传播许多传染病，例如疟疾，登革热 发烧和寨卡病毒。目前，使用杀虫剂控制媒介是防止 这些疾病的传播。鉴于杀虫剂在蚊子种群中的迅速传播， 必须在蚊子控制剂的武器库中添加具有不同作用模式的新杀虫剂。 少年激素（JH）信号通路是控制蚊子载体的有吸引力的目标。 JH是一个 蚊子开发和繁殖的关键调节剂。将成年蚊子暴露于吡啶芬，一个 合成的JH模拟物显示出有效对女性蚊子进行有效消毒的希望。我们这个项目的目标是 阐明JH使用的分子途径及其模仿来调节蚊子繁殖力。 蚊子发育主要由JH和20-羟基甲虫（20E）控制。在最后的资金中 循环，我们证明了耐甲酯耐受剂（Met）蛋白是JH的细胞内受体。两个都 天然JH和吡吡氧芬与伊蚊的结合具有高亲和力。 JH结合后，MET形式 Taiman的二聚体是JH和20E响应涉及的转录因子。大都会 复合物直接调节JH控制基因的表达。除了基因组动作，我们还 报道了从质膜引发的快速JH信号。依赖的非基因组动作 在受体酪氨酸激酶（RTK）上，调节了Metaiman复合物的DNA结合并调节 Taiman基因的替代剪接。而膜发射的JH信号至关重要 在蚊子繁殖，膜JH受体和特定RTK中的作用尚未确定 蚊子。我们最近的研究表明，一小部分MET与等离子体有关 蚊子细胞中的膜。此外，MET的耗尽消除了JH激活的增加 细胞内Ca2+，这是核外JH信号的一部分。因此，我们的结果表明膜 相关MET充当膜JH受体，可介导JH的非基因组作用。 在这项拟议的研究中，我们将检验以下假设：蚊子中的JH作用均由两者介导 膜结合和核元素质蛋白质，并且乙烯芬使用此JH信号通路来抑制 20E调节的基因表达。在AIM 1中，我们将定义膜在膜结合中的作用 JH和膜发射的JH信号传导。在AIM 2中，我们将调查膜大会如何介导 JH在蚊子中的非原位作用。在AIM 3中，我们将阐明吡吡氧芬如何利用JH信号传导 抑制20E植物生成的途径。这项研究将为我们的理解增加一个新的维度 蚊子繁殖所需的JH信号通路。它也可能揭示JH中的新目标 可以利用农药发展的信号通路。