Analysis of the functions of axon guidance genes during vector mosquito developme

媒介蚊发育过程中轴突引导基因的功能分析

• 批准号: 7904123
• 负责人: Molly Duman Scheel
• 金额: $ 37.92万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904123
• 关键词: Aedes; Animal Model; Anopheles gambiae; Appearance; Arthropod Vectors; Arthropods; Behavior; Biological Assay; Blood; Culicidae; DCC gene; Data; Dengue; Dengue Virus; Developed Countries; Developing Countries; Development; Developmental Gene; Developmental Process; Disease; Disease Outbreaks; Drosophila genus; Drosophila melanogaster; Drug resistance; Embryo; Epidemic; Gene Expression; Gene Proteins; Genes; Genetic; Genome; Goals; Human; Infection; Insect Vectors; Insecta; Insecticide Resistance; Investigation; Knowledge; Laboratories; Lead; Location; Malaria; Methods; Mosquito Control; Mosquito-borne infectious disease; Motor; Nervous system structure; Parasites; Population; Proteins; RNA; Regulation; Regulator Genes; Research; Role; Salivary Glands; Semaphorins; Sensory Process; Signal Transduction; Signaling Molecule; System; Testing; Tissues; Travel; Virus; Yellow Fever; Yellow fever virus; axon guidance; base; cell motility; comparative; developmental genetics; disorder control; feeding; fly; gene function; genetic analysis; genetic manipulation; gland development; human disease; interest; knock-down; nervous system development; plexin; prevent; programs; protein expression; public health relevance; receptor; receptor expression; receptor function; relating to nervous system; vaccine development; vector; vector mosquito

DESCRIPTION (provided by applicant): Mosquito-borne infectious diseases are an increasing global threat to humans. Blood-feeding mosquitoes transmit many of the world's deadliest diseases. Such diseases have resurged in developing countries and are also emerging as clear threats for epidemic outbreaks in developed countries. Numerous factors contribute to the current inability to prevent or control these diseases, including poor progress in vaccine development, the appearance of insecticide resistance in mosquito populations, the emergence of drug resistance in parasite populations, a general lack of support in many developing countries for mosquito control programs, and increased global travel. The mosquito genome projects have stimulated increased interest in the potential for arthropod-borne disease control by genetic manipulation of vector insects. Targets of particular interest include genes that regulate development. Analysis of genes that regulate mosquito nervous system development will lead to a better understanding of the developmental basis of motor function, sensory processing, and behavior, key aspects of mosquito host location. Furthermore, analysis of the development of mosquito salivary glands, which are essential for the spread of infection, could lead to creation of additional means of controlling mosquitoes. However, extremely little is known about the genetic regulation of these or other tissues during mosquito development. In recent years, evolutionary developmental biologists have applied knowledge of developmental genetics in Drosophila melanogaster, a genetically tractable model organism, to better understand development of other arthropods. Analysis of axon guidance molecules such as Netrins and Semaphorins in Drosophila indicate that these proteins regulate numerous developmental processes during fly development, including embryonic axon guidance, olfactory neural guidance, and salivary gland development. Preliminary data support the hypothesis that the roles of these genes are conserved in mosquitoes. Analysis of the functions of axon guidance genes in mosquitoes could therefore promote a better understanding of mosquito nervous system and salivary gland development. The specific aims of this investigation are to characterize the function of several axon guidance genes, including Netrin and its DCC receptor, and Semaphorin1a and its PlexinA receptor during mosquito development. These studies will include the yellow and dengue fever virus vector Aedes aegypti, as well as the malaria vector Anopheles gambiae. Methods that will be employed to test the hypothesis that axon guidance gene function is conserved in mosquitoes include gene and protein expression assays, as well as genetic knock-down strategies (RNA inhibition/morpholinos). Detailed analysis of the function of developmental regulatory genes and selective inhibition of such genes in mosquitoes is a requisite step toward attaining the long-term goals of this research program, which are to selectively target mosquito developmental genes in an effort to control mosquito-borne infectious diseases. PUBLIC HEALTH RELEVANCE: Although very little is known about the genes that regulate vector mosquito development, genetic analysis of mosquito development can reveal new targets for mosquito-control agents. The proposed research aims to analyze the function of several developmental regulatory genes in the dengue and yellow fever virus vector Aedes aegypti and the malaria vector Anopheles gambiae through analysis of gene expression and RNA inhibition studies. Results obtained in these studies will likely be applicable to other vector mosquitoes.

描述（由申请人提供）：蚊子传染病是对人类的日益增加的全球威胁。流血的蚊子传播了世界上许多最致命的疾病。这些疾病在发展中国家恢复了，也正逐渐成为发达国家流行病爆发的明显威胁。许多因素导致当前无法预防或控制这些疾病，包括疫苗开发的进展不佳，蚊子种群中杀虫剂耐药性的出现，寄生虫种群中耐药性的出现，许多发展中国家对蚊子控制程序的支持普遍缺乏支持以及增加全球旅行。蚊子基因组项目通过基因操纵媒介昆虫的遗传操纵来刺激对节肢动物传播疾病控制的潜力的兴趣。特别感兴趣的目标包括调节发展的基因。对调节蚊子神经系统发育的基因的分析将使人们更好地理解运动功能，感觉处理和行为的发展基础，这是蚊子宿主位置的关键方面。此外，分析蚊子唾液腺的发育对于感染的传播至关重要，可能导致创造其他控制蚊子的方法。但是，对于蚊子发育过程中这些或其他组织的遗传调节知之甚少。近年来，进化的发育生物学家应用了对遗传学模型有机体果蝇中的发育遗传学知识，以更好地了解其他节肢动物的发育。分析果蝇中的轴突引导分子，例如Netrins和Semaphorins，表明这些蛋白质在苍蝇发育过程中调节许多发育过程，包括胚胎轴突指导，嗅觉神经指导和唾液腺发育。初步数据支持以下假设：这些基因在蚊子中是保守的。因此，分析蚊子中轴突引导基因的功能可以促进对蚊子神经系统和唾液腺发育的更好理解。这项研究的具体目的是表征包括Netrin及其DCC受体在内的几个轴突引导基因的功能，以及在蚊子发育过程中Semaphorin1a及其Plexina受体的功能。这些研究将包括黄色和登革热病毒载体埃及埃及埃及以及疟疾载体冈比亚。将采用用于检验斧头引导基因功能在蚊子中保守的假设的方法包括基因和蛋白质表达测定，以及遗传敲低策略（RNA抑制/形态学）。详细分析发育调节基因的功能和对蚊子中此类基因的选择性抑制是实现该研究计划的长期目标的必要步骤，该计划将有选择地靶向蚊子发育基因，以控制蚊子 - 蚊子 - 涌现的感染性疾病。公共卫生相关性：尽管对调节向量蚊子发展的基因知之甚少，但蚊子开发的遗传分析可以揭示蚊子控制剂的新目标。拟议的研究旨在通过分析基因表达和RNA抑制研究的分析来分析登革热和黄热病病毒载体埃及埃及埃及和疟疾载体冈比亚的功能。在这些研究中获得的结果可能适用于其他媒介蚊子。