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 这项工作将涉及在Zika，Chikungunya和 登革热蚊子。埃及，人类昆虫传播疾病的主要媒介，已知每年感染至 全世界有5亿人口，住院超过½百万，约有25,000人丧生。电流 用于预防蚊子疾病的方法，包括通过环境修饰抑制媒介， 杀虫剂和抗炎药根本不足。更换野生蚊子 具有一般修改为“抗病性”的普遍修改的人的人群应提供 可持续，长期预防疾病的方法。但是，介导疾病的转基因 折磨不太可能为携带昆虫带来整体适应性益处。另外，野性 种群很大，部分生殖隔离，并分散在较大地区。因此，人口 替换需要一种基因驱动机制才能传播连锁的货物基因，介导疾病 通过野生病原体传播种群的耐火性。在这里，我建议“复活”历史 使用相互染色体易位将疾病疾病基因传播到野生病原体的概念 传播蚊子种群。尽管过去这种方法是严格尝试的，但最终是 由于用于产生的技术而产生的技术成本的提高，完全放弃了 易位菌株，除了将基因抗病性抗病与染色体联系起来外 断点。重要的是，基因工程和合成生物学的最新进展允许这些 历史问题完全克服。此外，转运介导的基因驱动系统是 依赖阈值，因此具有一些对社会和科学接受至关重要的有吸引力的功能 野生转基因释放：系统特定于规格；规格之间的零水平扩展；最小 与杀虫剂相比，生态影响；自私的不可分割的联系，坚固而坚不可摧 遗传元素及其货物；如果需要，可以从野生种群中完全转化。 因此，该项目将利用尖端应用的合成生物学原理来互动 AE精确位置的染色体易位。埃及（AIM-1）。一旦承重易位应变 建立，这些将通过野生遗传背景侵入，适应性动态将被衡量，并且 将执行小型实验室规模的驱动实验（AIM-2）。总体而言，成功的基于易位 与疾病难治基因相关的人口替代系统将对这两者产生重大影响 人类健康以及将来将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进行设计，因此这种创新的方法也可以在以后进行设计 广泛的绝缘疾病媒介，革新和现代化了绝缘种群控制领域。