Juvenile hormone action, and crosstalk between juvenile hormone and 20-hydroxyecd

保幼激素的作用以及保幼激素与 20-羟基ecd 之间的串扰

• 批准号: 8272970
• 负责人: JINSONG ZHU
• 金额: $ 32.83万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272970
• 关键词: Adult; Aedes; Affect; Affinity; Alanine; Amino Acid Substitution; Amino Acids; Binding; Biological; Biological Assay; Biological Process; Bite; Blood; Cells; Chemicals; Communicable Diseases; Complex; Culicidae; DNA Binding; Dengue Virus; Development; Disease; Drops; Ecdysterone; Egg Yolk Proteins; Electrophoretic Mobility Shift Assay; Fat Body; Female; Gene Expression; Gene Silencing; Gene Targeting; Genes; Goals; Homology Modeling; Hormone Receptor; Hormones; Hybrids; In Vitro; Incidence; Infection; Ingestion; Insect Hormones; Insect Vectors; Juvenile Hormones; Malaria; Mediating; Methoprene; Modeling; Molecular; Molecular Target; Mosquito Control; Mutagenesis; Mutation; Nucleic Acid Regulatory Sequences; Ovary; Parasites; Persons; Pesticides; Play; Population Control; Production; Property; Protein Binding; Protein Precursors; Proteins; RNA Interference; Recruitment Activity; Reporter; Role; Side; Signal Pathway; Signal Transduction; Structure; Techniques; Testing; Topical application; Transactivation; Transcriptional Activation; Vertebrates; Yeasts; base; chromatin immunoprecipitation; deprivation; design; disease transmission; ecdysteroid receptor; egg; emerging adult; feeding; hormone analog; hormone response element; meetings; novel; pathogen; prevent; promoter; protein protein interaction; receptor; response; steroid hormone; three-dimensional modeling; transcription factor; transmission process; uptake; vector control

DESCRIPTION (provided by applicant): Mosquitoes are insect vectors responsible for the transmission of many infectious diseases to hundreds of millions of people worldwide. Females of most mosquito species require blood from vertebrate animals for their egg development. Multiple bloodfeedings enable mosquitoes to transmit disease pathogens, including malaria parasites and dengue virus, from one person to another. Our long term goal of this project is to elucidate the molecular mechanisms that regulate mosquito egg production and identify target molecules that can be utilized for mosquito control. Mosquito egg development is governed by alternating peaks of two major insect hormones - juvenile hormone (JH) and 20-hydroxyecdysone (20E). Deprivation of JH in newly emerged adult female mosquitoes will halt egg maturation. On the other hand, topical application of JH to mosquitoes shortly after blood feeding interferes with the normal responses to 20E and impairs egg production. We have recently demonstrated that the mosquito Methoprene-tolerant (AaMet) protein is a key player in the juvenile hormone signaling pathway in the newly emerged adult female mosquitoes. AaMet protein binds to JH and forms a complex with AaFISC protein, a coactivator of the 20E receptor. AaMet and AaFISC are found to be associated with the promoters of JH target genes and activate their expression. In addition, our preliminary studies imply that AaMet mediates the inhibitory effects of JH on 20E-induced gene expression. Taken together, the results suggest that AaMet and AaFISC are components of a juvenile hormone receptor. The objective of this project is to elucidate the molecular details of how AaMet functions in juvenile hormone signaling that regulates egg maturation in mosquitoes. In Aim 1, we will perform structure-function studies of the juvenile hormone binding domain in AaMet and define the structural determinants required for high affinity binding to JH. In Aim 2, we will investigate how AaMet and AaFISC proteins are recruited to juvenile hormone response elements in the JH target genes. In Aim 3, we will test the hypothesis that AaMet is involved in the crosstalk between juvenile hormone and 20E signals in blood-fed female mosquitoes. The study will significantly advance our understanding of the molecular action of juvenile hormone in mosquitoes, and provide a structural basis for designing new pesticides that specifically target the mosquito JH signaling pathway. PUBLIC HEALTH RELEVANCE: The goal of this study is to elucidate the molecular mechanism by which the mosquito juvenile hormone regulates egg maturation in adult female mosquitoes. A better understanding of the hormone action at the molecular level is of paramount importance for designing new mosquito pesticides that specifically block the action of juvenile hormone, potentially disrupting all the biological processes in mosquitoes that are regulated by juvenile hormone.

描述（由申请人提供）：蚊子是昆虫媒介，负责将许多传染病传播给全世界数亿人。大多数蚊子种类的雌性需要脊椎动物的血液来发育卵。多次吸血使蚊子能够将疾病病原体从一个人传播到另一个人，包括疟疾寄生虫和登革热病毒。我们该项目的长期目标是阐明调节蚊卵产生的分子机制并确定可用于蚊子控制的目标分子。蚊子卵的发育受两种主要昆虫激素——保幼激素 (JH) 和 20-羟基蜕皮激素 (20E) 交替峰值的控制。剥夺新出现的成年雌性蚊子的 JH 会导致卵子成熟停止。另一方面，在吸血后不久向蚊子局部施用 JH 会干扰对 20E 的正常反应并损害产卵。我们最近证明，蚊子的甲虫酯耐受（AaMet）蛋白是新出现的成年雌性蚊子保幼激素信号通路中的关键角色。 AaMet 蛋白与 JH 结合并与 AaFISC 蛋白（20E 受体的共激活剂）形成复合物。 AaMet 和 AaFISC 被发现与 JH 靶基因的启动子相关并激活其表达。此外，我们的初步研究表明 AaMet 介导 JH 对 20E 诱导的基因表达的抑制作用。综上所述，结果表明 AaMet 和 AaFISC 是保幼激素受体的组成部分。该项目的目的是阐明 AaMet 如何在调节蚊子卵成熟的保幼激素信号传导中发挥作用的分子细节。在目标 1 中，我们将对 AaMet 中的保幼激素结合域进行结构功能研究，并定义与 JH 高亲和力结合所需的结构决定因素。在目标 2 中，我们将研究 AaMet 和 AaFISC 蛋白如何被招募到 JH 靶基因中的保幼激素反应元件中。在目标 3 中，我们将检验 AaMet 参与吸血雌性蚊子保幼激素和 20E 信号之间串扰的假设。这项研究将显着增进我们对保幼激素在蚊子体内分子作用的理解，并为设计专门针对蚊子 JH 信号通路的新型杀虫剂提供结构基础。 公共健康相关性：本研究的目的是阐明蚊子保幼激素调节成年雌性蚊子卵成熟的分子机制。在分子水平上更好地了解激素作用对于设计专门阻止保幼激素作用的新型灭蚊剂至关重要，可能会破坏蚊子中受保幼激素调节的所有生物过程。