Developing reciprocal chromosomal translocations for wild population replacement in an important vector of human disease.

开发相互染色体易位以替代人类疾病的重要媒介中的野生种群。

• 批准号: 9243803
• 负责人: Omar Sultan Akbari
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-19 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243803
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antimalarials; Appearance; Area; Beds; Bite; Breeding; Chemicals; Chromosomal Breaks; Chromosomal translocation; Chromosomes; Communicable Diseases; Complex; Cost of Illness; Coupled; Culicidae; Dengue; Dengue Vaccine; Development; Disease; Disease Resistance; Disease Vectors; Drug resistance; Ecology; Effectiveness; Engineering; Environment; Environmental Impact; Excision; Female; Frequencies; Future; Genes; Genetic; Genetic Engineering; Goals; Health; Human; Individual; Insect Vectors; Insecta; Insecticides; Laboratories; Link; Location; Malaria; Measures; Mediating; Methods; Modernization; Modification; Mosquito-borne infectious disease; Pharmaceutical Preparations; Plasmodium; Population; Population Control; Population Genetics; Population Replacements; Positioning Attribute; Prevention approach; Protective Clothing; Reapplication; Refractory; Refractory Disease; Resistance; Site; Structure; System; Target Populations; Technology; Transgenes; Transgenic Organisms; Vector-transmitted infectious disease; Work; Yellow Fever; Yellow Fever Vaccine; Zika Virus; base; chikungunya; combat; cost; design; disease transmission; disorder control; disorder prevention; experimental study; fitness; genetic element; genetic manipulation; human disease; innovation; insect disease; insect genetics; killings; mathematical model; pathogen; population based; prevent; repaired; reproductive; social; synthetic biology; vector; vector control

Abstract This work will involve the development of an invasive gene drive system in the Zika, Chikungunya, and Dengue mosquito, Ae. aegypti, a major vector of human insect-borne disease known to annually infect up to 500 million people worldwide, hospitalizing over ½ a million, and killing approximately 25,000. The current approaches used for mosquito disease prevention, including vector suppression by environmental modification, insecticides, and anti-inflammatory drugs, are simply insufficient. The replacement of wild mosquito populations with genetically modified individuals that are engineered to be “disease resistant” should provide a sustainable, long-term, method for disease prevention. However, the transgenes that mediate disease refractoriness are unlikely to confer an overall fitness benefit to insects that carry them. Additionally, wild populations are large, partially reproductively isolated, and dispersed over wide areas. Therefore, population replacement requires a gene drive mechanism in order to spread linked cargo genes, mediating disease refractoriness, through wild pathogen transmitting populations. Here I propose to “resurrect” the historical concept of using reciprocal chromosomal translocations to spread disease refractory genes into wild pathogen transmitting mosquito populations. While this approach was rigorously attempted in the past, it was ultimately completely abandoned, due to elevated fitness costs resulting from the technologies used to generate the translocation strains, in addition to the inabilities to link genes for disease resistance to the chromosomal break-points. Importantly, recent advancements in genetic engineering and synthetic biology allow for these historical problems to be entirely overcome. Furthermore, translocation-mediated gene drive systems are threshold-dependent and thus have several attractive features important for social and scientific acceptance for wild transgenic releases: the systems are species specific; zero horizontal spread between species; minimal ecological impact in contrast to insecticides; robust and unbreakable with a inexorable linkage of the selfish genetic element with its cargo; complete transgene removal from wild population can be carried out if desired. Therefore, this project will utilize cutting-edge applied synthetic biology principals to engineer reciprocal chromosomal translocations at precise locations in Ae. aegypti (Aim-1). Once translocation-bearing strains are established, these will be introgressed with wild genetic backgrounds, fitness dynamics will be measured, and small laboratory-scale drive experiments will be executed (Aim-2). Overall, a successful translocation-based population replacement system linked with disease refractory genes will have a significant impact on both human health and the technical capability in which mosquitoes and other insects will be managed in the future. As these systems can be designed in most insects, this innovative approach could also later be engineered in wide range of insect disease vectors, revolutionizing and modernizing the field of insect population control.

抽象的 这项工作将涉及寨卡病毒、基孔肯雅病毒和其他疾病的侵入性基因驱动系统的开发。 登革热蚊子，埃及伊蚊，是人类昆虫传播疾病的主要媒介，每年感染多达 目前全球有 5 亿人，超过 100 万人住院，约 25,000 人死亡。 用于预防蚊子疾病的方法，包括通过改变环境来抑制病媒， 杀虫剂和消炎药根本不足以替代野生蚊子。 具有“抗病”能力的转基因个体的种群应该提供 可持续的、长期的疾病预防方法然而，介导疾病的转基因。 耐火性不太可能给携带它们的昆虫带来整体健康益处。 人口数量众多，部分生殖隔离，并且分布广泛。 替代需要基因驱动机制来传播相关的货物基因，介导疾病 在这里，我建议通过野生病原体传播群体来“复活”历史。 利用染色体相互易位将疾病难治性基因传播到野生病原体中的概念 虽然过去曾严格尝试过这种方法，但最终还是失败了。 由于用于产生能量的技术导致健身成本增加，因此完全被放弃 易位菌株，除了无法将抗病基因与染色体连接起来之外 重要的是，基因工程和合成生物学的最新进展允许这些。 此外，易位介导的基因驱动系统正在被彻底克服。 阈值依赖性，因此具有几个对社会和科学接受度很重要的有吸引力的特征 野生转基因释放：该系统具有物种特异性；物种之间的水平传播最小； 与杀虫剂相比，对生态的影响强大且牢不可破，与自私有着不可分割的联系 遗传元件及其货物；如果需要，可以从野生种群中完全去除转基因。 因此，该项目将利用尖端的应用合成生物学原理来设计互惠 埃及伊蚊 (Aim-1) 中精确位置的染色体易位。 建立后，这些将被引入野生遗传背景，将测量适应性动态，并且 将进行小型实验室规模的驱动实验（Aim-2）总体而言，基于易位的成功。 与疾病难治基因相关的人口更替系统将对两者产生重大影响 人类健康以及未来管理蚊子和其他昆虫的技术能力。 由于这些系统可以在大多数昆虫中设计，这种创新方法也可以在以后设计 广泛的昆虫疾病媒介，使昆虫种群控制领域发生革命性和现代化。