Genome-based diagnostics for monitoring and evaluation of insecticide resistance in Anopheles gambiae

基于基因组的诊断用于监测和评估冈比亚按蚊杀虫剂抗药性

基本信息

批准号：
9029400
负责人：
Martin James Donnelly
金额：
$ 49.75万
依托单位：
TMLIVERPOOL SCHOOL OF TROPICAL MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029400
关键词：
Address Affect Africa Africa South of the Sahara Anopheles Genus Anopheles gambiae Area Bioinformatics Biological Assay Cessation of life Chemicals Collection Communities Complex Computer Simulation Computers Country Culicidae DNA DNA Markers Data Data Set Databases Development Diagnostic Economic Development Evaluation Frequencies Future Generations Genes Genetic Genome Genomics Goals Insecticide Resistance Insecticides Institutes Intervention Knowledge Laboratories Licensing Link Malaria Maps Measures Methodology Methods Modeling Monitor Morbidity - disease rate Mosquito Control Nucleic Acid Regulatory Sequences Phase Phenotype Play Population Predictive Value Property Research Research Personnel Research Project Grants Residual state Resistance Resources Role Sampling Specimen Testing Trust Uncertainty Variant Work base biomarker panel design diagnostic biomarker genome sequencing malaria infection molecular marker mortality novel novel marker operation prevent programs public health relevance research study resistance mechanism scale up screening secondary outcome success tool user-friendly vector vector control whole genome

项目摘要

DESCRIPTION (provided by applicant): Malaria is a major cause of mortality and morbidity in Sub-Saharan Africa (SSA) and one of the biggest impediments to the economic development of the region. Malaria is transmitted by Anopheles mosquitoes and one of the major methods for controlling these mosquitoes is through the use of chemical insecticides. Unfortunately, there are only four chemical classes of insecticides licensed for used for mosquito control, and resistance has already emerged to all classes although with a marked difference in levels. This resistance is a major threat to the recent advances the malaria control community has made in reducing both deaths and malaria infections. To reduce the impact of resistance, malaria control program managers need to know when resistance is emerging in their intervention areas and put in place measures to prevent its spread e.g. switching to a new insecticide. The most effective way of doing this is through the use of DNA markers which can detect the presence of a resistance associated marker in a mosquito population before it reaches high frequency. It is the primary goal of this proposal to revolutionize the application of molecular markers for insecticide resistance across the malaria endemic countries of SSA by providing control programs with new markers and geographically-calibrated maps that predict their impact on resistance phenotypes. The unifying theme of this project is to exploit the power of whole genome sequencing to identify genes/regulatory regions that are associated with insecticide resistance. We will use a combination of approaches including computer-based searches of existing genome data bases; large scale collections and resistance screening of malaria mosquitoes in both East and West Africa, and laboratory crossing experiments to identify rare, resistance-associated variants. All these studies will be underpinned by extensive whole genome sequencing performed by the Wellcome Trust Sanger Institute. A major secondary outcome of this project will be the release of these genome data sets to the research community which will be a powerful resource for vector biologists. Once we have identified resistance-associated DNA markers we will calibrate their links with resistance and then map their frequencies and distributions in expanded collections of mosquitoes provided by a network of collaborators in SSA. We will use modelling approaches to produce marker maps from these data, including the sensitivity of their predictive power to key environmental variables. Our project will develop and apply new bioinformatic, laboratory and field methodologies to identify DNA markers and associated mapping resources for current and future insecticides, providing long-term insecticide resistance management tools for control programs.

描述（由适用提供）：疟疾是撒哈拉以南非洲（SSA）死亡率和发病率的主要原因，也是该地区经济发展的最大障碍之一。疟疾是通过蚊子传播的，控制这些蚊子的主要方法之一是使用化学绝缘。不幸的是，只有四种用于用于蚊子控制的绝缘材料的化学类别类别，尽管有明显的水平差异，但已经出现了对所有类别的阻力。这种抵抗是对疟疾控制社区最近减少死亡和疟疾感染方面所取得的主要发展的主要威胁。为了减少抵抗的影响，疟疾控制计划经理需要知道何时在干预区域出现阻力，并采取措施防止其传播，例如切换到新的杀虫剂。这样做的最有效方法是通过使用DNA标记，该标记可以在达到高频之前检测蚊子种群中抗性相关标记的存在。这项提案的主要目标是通过为SSA的疟疾内象国家抗杀虫剂的抗性分子标记的应用，通过提供新标记和地理校准图的控制程序来预测其对抵抗表型的影响。该项目的统一主题是利用整个基因组测序的力量来识别与杀虫剂耐药性相关的基因/调节区域。我们将使用多种方法组合，包括基于计算机的现有基因组数据库的搜索；东非和西非的疟疾蚊子的大规模收集和耐药性筛查，以及实验室穿越实验，以鉴定罕见的抗性相关变体。所有这些研究将由Wellcome Trust Sanger Institute进行的广泛的整个基因组测序基础。该项目的主要次要结果将是将这些基因组数据集发布给研究界，这将是向量生物学家的强大资源。一旦确定了与电阻相关的DNA标记，我们将用阻力校准其链接，然后在SSA的合作者网络提供的扩展的蚊子集合中绘制其频率和分布。我们将使用建模方法从这些数据中产生标记图，包括其预测能力对关键环境变量的敏感性。我们的项目将开发并应用新的生物信息学，实验室和现场方法，以识别当前和将来绝缘的DNA标记和相关的映射资源，从而为控制程序提供长期绝缘管理工具。