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Characterizing the role of the 22 up-regulated genes in mosquito resistance

表征 22 个上调基因在蚊子抗性中的作用

基本信息

批准号：
7828014
负责人：
NANNAN LIU
金额：
$ 25.55万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-08 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7828014
关键词：
Adult Applications Grants Carrier Proteins Complex Culex (Genus)Culicidae Cytochrome P450 Family Gene Drug Metabolic Detoxication Exhibits Figs - dietary Gene Amplification Gene Expression Gene Expression Regulation Gene Family Generations Genes Glutathione S-Transferase Goals Human Individual Insecta Insecticide Resistance Insecticides Laboratories Malaria Measures Mediating Metabolic Metabolism Mixed Function Oxygenases Molecular Molecular Profiling Mosquito Control Mosquito-borne infectious disease Organism Permethrin Polymerase Chain Reaction Protein Biosynthesis Proteins RNA RNA Interference Regulation Regulator Genes Research Research Project Grants Resistance Resistance development Reverse Transcription Role Schedule Signal Transduction Techniques Testing Time Tissue-Specific Gene Expression Transferase Gene Transport Process Ubiquitination Up-Regulation cDNA Arrays disorder control enzyme activity esterase gene function gene interaction novel novel strategies offspring protein expression public health relevance pyrethroid resistance mechanism resistant strain response vector mosquito

项目摘要

DESCRIPTION (provided by applicant): Mosquito-borne diseases are the number-one killers of humans worldwide. A major obstacle in controlling these diseases is that mosquitoes have developed resistance to insecticides. Our long-term goals are to determine the roles of genes that control the mosquito's response to insecticides and to use this information to develop novel approaches to control mosquito vectors. A large number of studies has shown that multiple, complex mechanisms or genes may be responsible for insecticide resistance. However, many questions remain, including these 2 that we seek to answer: 1) how many detoxification gene families and individual genes are involved in insecticide resistance in a single organism, such as the mosquito? And 2) are there genes, in addition to metabolic detoxification genes, the up-regulation of which confers resistance? The Liu laboratory has recently identified 22 novel genes that are over-expressed in Culex HAmCq mosquitoes. These genes are known to be vital for cellular and molecular metabolism, signal transduction and regulation, vesicular and molecular transport, and protein biosynthesis and ubiquitination, but most of them have not been implicated in insecticide resistance. The objective of the proposed project is to determine the potential roles of the 22 up-regulated genes in insecticide resistance in mosquitoes. Our hypothesis is that among the 22 up-regulated genes in our study, the genes involved in insecticide resistance (the key genes) exhibit increased expression, increased protein activities, and increased protein expression following insecticide selection. Our specific aims are to: 1) Define the relationship between the levels of resistance and the levels of gene expression, enzyme activity, and protein expression in each of the 22 up-regulated genes in the susceptible S-Lab strain; the field permethrin-resistant strains of HAmCqG0, MAmCqG0, and BAmCqG0; 8 generations of permethrin-selected HAmCqG0 offspring (HAmCqG1 to HAmCqG8); and the 8th generation of the permethrin-selected S-Lab strain (S-Lab-PerG8) and 2) Determine the relationship between the silenced expression levels of key genes in HAmCqG8 and their corresponding levels of insecticide resistance. Characterizing roles of the 22 up-regulated genes in insecticide resistance is a necessary and fundamental first step in determining resistance mechanisms, understanding the function of these genes in mosquito insecticide resistance, and ultimately providing important new information that can be used for basic studies of resistance-gene interaction and regulation, and for applied studies in developing novel approaches for controlling mosquitoes. PUBLIC HEALTH RELEVANCE The proposed project seeks to identify the role of up-regulated genes in insecticide resistance in mosquitoes by defining the relationship between the levels of resistance and the levels of gene expression, enzyme activity, and protein expression of the up-regulated genes in the following strains: the susceptible S-Lab strain, the field permethrin resistant strains (HAmCqG0, MAmCqG0, and BAmCqG0), 8 generations of permethrin-selected HAmCqG0 offspring (HAmCqG1 to HAmCqG8); and the 8th generation of permethrin-selected S-Lab strain (S-Lab-PerG8). We will silence (reduce) the expression of key genes in HAmCqG8 to determine their functions in insecticide resistance.

描述（由申请人提供）：蚊子传播的疾病是全世界人类的头号杀手。控制这些疾病的一个主要障碍是蚊子对杀虫剂产生了抗药性。我们的长期目标是确定控制蚊子对杀虫剂反应的基因的作用，并利用这些信息开发控制蚊子媒介的新方法。大量研究表明，多种复杂的机制或基因可能是造成杀虫剂抗药性的原因。然而，许多问题仍然存在，包括我们试图回答的这两个问题：1）在单一生物体（如蚊子）中，有多少解毒基因家族和个体基因参与杀虫剂抗性？2）除了代谢解毒基因外，是否有基因的上调赋予了抵抗力？Liu实验室最近发现了22个在库蚊HAmCq中过度表达的新基因。已知这些基因对于细胞和分子代谢、信号转导和调节、囊泡和分子运输以及蛋白质生物合成和泛素化至关重要，但它们中的大多数与杀虫剂抗性无关。该项目的目的是确定22个上调基因在蚊子抗药性中的潜在作用。我们的假设是，在我们的研究中的22个上调基因中，参与杀虫剂抗性的基因（关键基因）表现出表达增加，蛋白质活性增加，以及杀虫剂选择后蛋白质表达增加。我们的具体目标是：1）确定敏感S-Lab菌株中的抗性水平与22个上调基因中的每一个的基因表达水平、酶活性和蛋白质表达水平之间的关系; HAmCqG 0、MAmCqG 0和BAmCqG 0的田间二氯苯醚菊酯抗性菌株; 8代二氯苯醚菊酯选择的HAmCqG 0后代（HAmCqG 1至HAmCqG 8）;和氯菊酯选择的S-Lab菌株的第8代（S-Lab-PerG 8）;和2）确定HAmCqG 8中关键基因的沉默表达水平与其相应的杀虫剂抗性水平之间的关系。鉴定22个上调基因在杀虫剂抗性中的作用是确定抗性机制、了解这些基因在蚊子杀虫剂抗性中的功能的必要和基本的第一步，并最终提供重要的新信息，可用于抗性基因相互作用和调控的基础研究，以及用于开发新的控制蚊子的方法的应用研究。公共卫生相关性拟议的项目旨在通过确定以下菌株中抗性水平与上调基因的基因表达水平、酶活性和蛋白质表达水平之间的关系，确定上调基因在蚊子杀虫剂抗性中的作用：敏感的S-Lab菌株、田间氯菊酯抗性菌株（HAmCqG 0、MAmCqG 0和BAmCqG 0），8代氯菊酯选择的HAmCqG 0后代（HAmCqG 1至HAmCqG 8）;和第8代氯菊酯选择的S-Lab菌株（S-Lab-PerG 8）。我们将沉默（减少）HAmCqG 8中关键基因的表达，以确定它们在杀虫剂抗性中的功能。