Developing Anti-viral Ribozymes to Suppress Arboviruses in Transgenic Mosquitoes

开发抗病毒核酶来抑制转基因蚊子中的虫媒病毒

基本信息

批准号：
8581314
负责人：
Malcolm J. FRASER
金额：
$ 56.3万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581314
关键词：
Aedes Affect Alphavirus Antisense Oligonucleotides Antiviral Agents Apoptosis Arbovirus Infections Arboviruses Arthropod Vectors Attention Catalytic RNA Cell Culture Techniques Cells Cessation of life Cleaved cell Climate Commerce Conserved Sequence Coupled Culicidae DNA Polymerase III Dengue Disease Double-Stranded RNA Drug resistance Effectiveness Ensure Enzymes Exons Flavivirus Genes Genetic Genome Goals Health Hepatitis D Human Immunization Infection Insecta Introns Mediating Population Population Replacements Public Health RNA RNA Interference Refractory Research Resistance Safety Testing Time Transgenes Transgenic Organisms Travel Urbanization Vaccines Viral Virus Virus Diseases Yellow Fever chikungunya cost effectiveness disease transmission hammerhead ribozyme improved novel strategies pathogen prevent programs success transgene expression transmission process vaccination strategy vector vector control vector mosquito

项目摘要

DESCRIPTION (provided by applicant): Chikungunya (CHIKV), yellow fever (YFV), and Dengue (DENV) are among the most troublesome human health pathogens responsible for hundreds of millions of infections and hundreds of thousands of deaths each year. They are transmitted to human populations by a single mosquito species, Aedes aegypti. Effective human vaccines are not yet available for CHIK, and DENV, and the re-emergence of YFV as a lethal pathogen, in spite of the availability of an effective vaccine, suggests ineffectiveness of vaccination strategies for sustained eradication. Interference with the incubation arboviruses within the arthropod vector is receiving considerable attention as a way to interrupt the viral transmission cycle and reduce the efficiency of transmission to humans. One such approach envisions population replacement of susceptible mosquitoes with those resistant to infection or to halt disease transmission. This approach has distinct advantages of environmentally safety, cost effectiveness, and long-term disease suppression. Transgenic introduction of expressed anti-viral molecules to generate refractoriness in the mosquito vector is now a real possibility. Recent successes reflected in the RIDL approach show significant promise, and can reasonably be expected to be coupled with transgenic refractoriness to establish and maintain transgene effectors in rebound mosquito populations. However, this avenue must necessarily be coupled with ensuring both long term effectiveness and stable transgene expression. Our research is demonstrating that ribozyme (RNA-enzyme) mediated viral suppression can provide an effective means of transgenic immunization against viruses. Recent efforts have confirmed the effectiveness of hammerhead ribozymes and Group I introns in suppressing DENV infection in mosquito cells. The research proposed seeks to build upon our successes in developing anti-viral ribozymes as potent effector genes against arbovirus infections in mosquitoes. In particular, this proposal will focus on developing, optimizing, and validating effective ribozyme suppression strategies against three major emerging and re-emerging disease pathogens vectored by the same mosquito species, Aedes aegypti, DENV, CHIKV, and YF. The ultimate goal is to be able to provide mosquito strains that will be useful in simultaneously eliminating two or more of these viral diseases.

描述（由申请人提供）：Chikungunya（Chikv），黄热病（YFV）和登革热（DENV）是每年造成数亿感染和数十万死亡的最麻烦的人类健康病原体之一。它们是由单个蚊子埃及埃及的单个蚊子传播到人类种群的。 CHIK和DENV尚未获得有效的人类疫苗，尽管有效的疫苗可用，但YFV作为致命病原体的重新出现表明，疫苗接种策略无效以持续消除。干扰节肢动物载体中的孵育弧病毒正在引起大量关注，以此作为中断病毒传播周期并降低向人类传播的效率的一种方式。一种这样的方法设想，人口替代了易感蚊子，那些对感染有抵抗力或阻止疾病传播的蚊子。这种方法具有环境安全，成本效益和长期抑制的明显优势。转基因引入表达的抗病毒分子以在蚊子载体中产生折射率是一种实际可能性。 RIDL方法中反映的最新成功表现出巨大的希望，并且可以合理地期望与转基因难治性相结合，以建立和维持回弹蚊子种群中的转基因效应子。但是，该途径必须与确保长期有效性和稳定的转基因表达相结合。我们的研究表明，核酶（RNA-酶）介导的病毒抑制可以提供对病毒的转基因免疫的有效手段。最近的努力证实了锤头核酶和I组内含子在抑制蚊子细胞中DENV感染中的有效性。拟议的研究试图基于我们在开发抗病毒核酶作为针对蚊子感染的有效效应基因方面取得的成功。特别是，该提案将着重于开发，优化和验证有效的核酶抑制策略，以针对由同一蚊子埃德斯埃及埃及埃及，denv，chikv和yf的三种主要出现和重新出现的疾病病原体。最终目标是能够提供蚊子菌株，这些蚊子可在消除两种或多种病毒疾病的同时有用。