CAREER: Genetic and Molecular Mechanisms of Parasite Infection in Insects

职业：昆虫寄生虫感染的遗传和分子机制

• 批准号: 1453287
• 负责人: Jun Li
• 金额: $ 78.34万
• 依托单位: University of Oklahoma Norman Campus
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1453287&HistoricalAwards=false
• 关键词: CAREER; Genetic; Molecular; Mechanisms; Parasite

Many parasites require obligatory insect hosts as part of their life cycle. Understanding the biology of host-parasite interactions, particularly at the genetic and molecular levels of analysis, is an important area of basic research because we lack an understanding of the principles of these interactions. Parasites with insect hosts must overcome insect innate immune defenses to be able to complete their life cycles, including development in the host and transmission. The molecular mechanisms underlying these interactions, and the genetic basis for variation in these interactions, are not fully understood. This project focuses on understanding host-parasite interactions in the mosquito Anopheles gambiae and the malaria-causing parasite Plasmodium falciparum to gain improved understanding of fundamental host-parasite interactions. The investigator has linked some host genetic variation with variation in the number of parasite life stages in the host, indicating variable immunity among individual insect hosts and therefore potentially differential ability to transmit the parasite. This researcher has developed a novel, computational approach to identify additional host genes associated with parasite infection, which enables the investigation of such genetic variation in immunity to parasites in natural populations of An. Gambiae, which can be more informative than studies in laboratory populations. The investigator will employ modern genomic, biochemical and computational methods in this study. This project will improve our knowledge base about the genetic basis of, and the molecular mechanisms of insect innate immunity against parasites, and more generally host-parasite interactions. An important broader scientific and societal impact of this study is improved understanding of the specific mosquito-parasite system that causes the disease malaria, which causes suffering and death in millions of people each year.Genetic analyses have demonstrated that genetic variation in Anopheles gambiae is associated with the number of Plasmodium oocysts in mosquitoes. Identifying the genes associated with variation in infection intensity and understanding how they function are important in decoding the genetic and molecular basis of insect-parasite interaction. Targeting these genes will lead to novel approaches in controlling parasite transmission. However, it is difficult to determine causative mutations from ~300 million base pairs and ~15,000 genes in the mosquito genome using traditional approaches. In a recent, significant finding, the Principal Investigator and co-workers used a novel computational approach and identified approximately 1% of the An. gambiae genome that is enriched with genes related to P. falciparum infection in mosquitoes. This research project is aimed at analysis of these newly identified genomic regions to elucidate molecular mechanisms of insect-parasite interaction using the well-characterized An. gambiae populations and P. falciparum parasites from western Kenya. Direct association studies will be systematically conducted to detect genetic variations associated with P. falciparum infection intensity in wild A. gambiae populations from Africa. Then the relative role of the candidate mosquito genes on parasite invasion will be determined under laboratory conditions and in the wild in Africa. Finally, the molecular mechanisms of candidate genes will be investigated. The combination of computational approaches, molecular functional analyses in the laboratory, and field entomology studies is a very powerful set of tools to address insect-parasite interactions. This CAREER project will integrate research and education from K-12 to graduate students, locally, nationally and internationally. K-12 students and teachers will have opportunities to learn and participate in genomics research with the investigators in this study. Seminars on insect-parasite interactions will be provided in local schools and universities. The educational seminars will also be given to the communities in Kenya where P. falciparum infection is endemic. While undergraduate and graduate students play important roles in the research, the research program also provides materials and resources for education in classrooms. Ultimately, an outstanding research program coupled with an excellent genomics curriculum will be established.

许多寄生虫需要强制性的昆虫宿主作为其生命周期的一部分。了解宿主 - 寄生虫相互作用的生物学，尤其是在遗传和分子分析水平上，是基础研究的重要领域，因为我们对这些相互作用的原理缺乏了解。带有昆虫宿主的寄生虫必须克服昆虫先天免疫防御能力，以便能够完成其生命周期，包括宿主的发展和传播。这些相互作用的分子机制以及这些相互作用变异的遗传基础尚未完全了解。该项目的重点是理解冈比亚蚊帐中的宿主 - 寄生虫相互作用和疟疾引起疟疾的寄生虫疟原虫恶性疟原虫，以提高人们对基本宿主 - 寄生虫相互作用的了解。研究者将一些宿主遗传变异与宿主寄生虫生命阶段的变化联系起来，表明单个昆虫宿主之间的免疫力可变，因此可能具有传播寄生虫的潜在差异能力。该研究人员开发了一种新型的计算方法，以鉴定与寄生虫感染相关的其他宿主基因，从而可以研究AN的自然种群中对寄生虫免疫的这种遗传变异。冈比亚，这比实验室人群中的研究更具信息性。研究人员将在本研究中采用现代基因组，生化和计算方法。该项目将提高我们对昆虫先天免疫的遗传基础的知识基础以及对寄生虫的分子机制，以及更普遍的宿主 - 寄生虫相互作用。这项研究的一个重要的更广泛的科学和社会影响是对引起疾病疟疾的特定蚊子 - 寄生虫系统的理解，这每年会导致数百万人中的痛苦和死亡。基因分析已经证明，冈比亚的Anopheles遗传变异与蚊子中嗜蚊的数量有关。识别与感染强度变化相关的基因，并了解它们的功能在解码昆虫 - 寄生虫相互作用的遗传和分子基础上很重要。靶向这些基因将导致控制寄生虫传播的新方法。但是，很难使用传统方法确定蚊子基因组中约3亿碱基对和约15,000个基因的致病突变。在最近的重大发现中，主要研究者和同事使用了一种新颖的计算方法，并确定了大约1％的A。冈比亚基因组富含与恶性疟原虫感染相关的基因。该研究项目旨在分析这些新鉴定的基因组区域，以使用特征良好的AN阐明昆虫 - 寄生虫相互作用的分子机制。来自肯尼亚西部的冈比亚人口和恶性疟原虫。直接关联研究将进行系统地进行，以检测来自非洲野生抗体群人群中与恶性疟原虫感染强度相关的遗传变异。然后，将在实验室条件下和非洲的野外确定候选蚊子基因在寄生虫入侵中的相对作用。最后，将研究候选基因的分子机制。计算方法，实验室中的分子功能分析以及现场昆虫学研究的结合是解决昆虫 - 寄生虫相互作用的非常强大的工具。该职业项目将在本地，国际和国际上将K-12与研究生的研究和教育整合在一起。 K-12学生和老师将有机会与研究人员一起学习和参与基因组学研究。当地学校和大学将提供有关昆虫寄生虫相互作用的研讨会。教育研讨会也将向肯尼亚的肯尼亚社区进行，那里的恶性疟原虫感染是地方性的。在本科生和研究生在研究中发挥重要作用的同时，研究计划还为教室提供了教育材料和资源。最终，将建立一项出色的研究计划，并建立出色的基因组学课程。