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.

项目概要 蚊子是疟疾、登革热等许多传染病的传播源 发烧和寨卡病毒。使用杀虫剂控制病媒生物是目前预防该病的主要手段 这些疾病的传播。鉴于蚊子种群对杀虫剂耐药性的迅速蔓延， 当务之急是在灭蚊剂库中增加具有不同作用方式的新杀虫剂。 保幼激素（JH）信号通路是控制蚊媒的一个有吸引力的靶点。 JH 是一个 蚊子发育和繁殖的关键调节因子。成年蚊子接触吡丙醚（吡丙醚） 合成的 JH 模拟物已显示出能够有效使雌性蚊子绝育的希望。我们这个项目的目标是 阐明 JH 及其模拟物用来调节蚊子繁殖力的分子途径。 蚊卵发育主要受JH和20-羟基蜕皮酮（20E）的控制。在上一次融资中 循环中，我们证明了Methoprene-耐受（MET）蛋白是JH的细胞内受体。两个都 天然 JH 和吡丙醚以高亲和力与埃及伊蚊 MET 结合。与 JH 结合后，MET 形成 与 Taiman 形成二聚体，Taiman 是一种参与 JH 和 20E 反应的转录因子。 MET-泰曼 复合物直接调节 JH 控制基因的表达。除了基因组作用外，我们还 报道了从质膜启动的快速 JH 信号传导。非基因组作用，依赖于 作用于受体酪氨酸激酶 (RTK)，调节 MET-Taiman 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 信号传导至关重要 膜 JH 受体和特定 RTK 在蚊子繁殖中的作用尚未确定 蚊子。我们最近的研究表明，一小部分 MET 与血浆有关 蚊子细胞内的膜。此外，MET的消耗消除了JH激活的增加 细胞内 Ca2+，是核外 JH 信号传导的一部分。因此，我们的结果表明膜 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，我们将检验以下假设：蚊子中的 JH 作用是由两者介导的 膜结合和核 MET 蛋白，吡丙醚利用此 JH 信号通路来抑制 20E调节的基因表达。在目标 1 中，我们将定义膜 MET 在膜结合中的作用 JH 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 抑制卵黄生成 20E 反应的途径。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。它还可能揭示 JH 中的新目标 可用于农药开发的信号通路。