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: 10373049
• 负责人: JINSONG ZHU
• 金额: $ 40.36万
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373049
• 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; Reproduction; Resistance; Role; Signal Pathway; Site; Specificity; Testing; Time; Tissues; Toxic effect; Zika Virus; base; dimer; disease transmission; ecdysteroid receptor; egg; hormonal signals; improved; knock-down; mosquito reproduction; non-genomic; prevent; promoter; protein aminoacid sequence; pyrethroid; receptor; response; screening; 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 蚊子是许多传染病的传播媒介，如疟疾、登革热 发烧和寨卡病毒使用杀虫剂控制病媒是目前预防疟疾的主要手段。 这些疾病的传播。鉴于蚊子对杀虫剂的抗药性迅速蔓延， 因此，有必要在蚊子控制剂的武库中增加具有不同作用模式的新杀虫剂。 保幼激素（JH）信号通路是一个有吸引力的目标，为控制蚊媒。JH是 蚊子发育和繁殖的关键调节因子。成年蚊子接触吡丙醚， 合成JH模拟物已经显示出有效地使雌性蚊子绝育的前景。我们这个项目的目标是 阐明JH及其模拟物调节蚊子繁殖力的分子途径。 蚕卵的发育主要受JH和20-羟基蜕皮激素（20 E）的调控。在上一次融资中， 循环，我们证明了甲氧普仑耐受（MET）蛋白是JH的细胞内受体。两 天然JH和吡丙醚以高亲和力结合埃及伊蚊MET。JH结合后，MET形成 二聚体与Taiman，一种参与JH和20 E反应的转录因子。MET-泰曼 复合物直接调节JH控制的基因的表达。除了基因组作用，我们还 报道了一种从质膜开始的快速JH信号传导。非基因组作用， 在受体酪氨酸激酶（RTK）上，调节MET-泰曼复合物的DNA结合，并调节 泰曼基因的选择性剪接。虽然膜启动的JH信号传导在细胞内起着至关重要的作用 在蚊子繁殖中的作用，膜JH受体和特异性RTK尚未被确定， 蚊子我们最近的研究表明，一小部分MET与血浆 蚊子细胞的膜。此外，MET的消耗根除了JH激活的 细胞内Ca ~（2+），这是细胞核JH信号传导的一部分。因此，我们的研究结果表明，膜- 相关的MET作为膜JH受体介导JH的非基因组作用。 在这项拟议的研究中，我们将测试的假设，JH行动在蚊子是介导的， 膜结合和核MET蛋白，吡丙醚使用这种JH信号通路来抑制 20 E调控的基因表达。在目标1中，我们将定义膜MET在膜结合中的作用。 和膜启动的JH信号传导。在目标2中，我们将研究膜MET如何介导 JH在蚊子中的非基因组作用。在目标3中，我们将阐明吡丙醚如何利用JH信号传导 途径抑制卵黄发生20 E反应。这项研究将为我们的理解增加一个新的层面 蚊子繁殖所需的JH信号通路。它还可能揭示JH中的新目标 信号通路，可用于农药开发。