Translational Regulation of Mosquito mRNAs during Plasmodium Infection

疟原虫感染期间蚊子 mRNA 的翻译调控

• 批准号: 7739063
• 负责人: JINSONG ZHU
• 金额: $ 22.66万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739063
• 关键词: Address; Adopted; Affect; Africa; Anopheles Genus; Anopheles gambiae; Biological Models; Blood; Cessation of life; Competence; Complement; Complex; Culicidae; Density Gradient Centrifugation; Development; Female; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic Translation; Goals; Human; Individual; Infection; Ingestion; Knowledge; Lead; Life; Malaria; Measurement; Measures; Messenger RNA; Methodology; Microarray Analysis; Midgut; Molecular; Molecular Profiling; Monitor; Parasites; Parasitic Diseases; Plasmodium; Plasmodium falciparum; Play; Polyribosomes; Predisposition; Protein Biosynthesis; Proteins; Proteome; Refractory; Regulation; Research; Ribosomes; Role; Series; Staging; Sucrose; Translating; Translational Regulation; Translations; base; feeding; genetic manipulation; genome wide association study; genome-wide; genome-wide analysis; insight; messenger ribonucleoprotein; novel strategies; particle; pathogen; public health relevance; response; transmission process; vector; vector mosquito

DESCRIPTION (provided by applicant): Malaria is the world's most important tropical parasitic disease. It is responsible for 2 percent of all deaths worldwide and 9 percent of deaths in Africa. More than 3 billion people live under the threat of malaria. The ability of mosquitoes to transmit malaria parasites varies among different mosquito species, even between different geographical strains of the same species. Our long term goal is to identify mosquito genes that play central roles in imparting susceptibility or refractoriness of mosquitoes to the malaria parasite Plasmodium, and to use this knowledge to aid future efforts to control malaria transmission. Understanding molecular details of the parasite-vector interactions relies heavily on precise measurement of nascent protein synthesis in the mosquito during Plasmodium infection. Current expression profiling largely monitors alterations in steady-state levels of mRNA. However, due to various post-transcriptional and translational regulatory mechanisms, the abundance of each given mRNA in the transcriptome does not necessarily mirror the expression of the encoded proteins within the proteome. Some mosquito factors might have gone unrecognized because they are translationally rather than transcriptionally regulated after mosquitoes ingest a Plasmodium-infected blood meal. This research plan combines mRNA profiling with genome-wide analysis of mRNA translation states to simultaneously monitor changes in the transcriptome and nascent protein synthesis in the mosquito. We will use sucrose density gradient centrifugation to separate mRNAs associated with polyribosomes from those that are translationally inactive. The mRNA levels of individual mosquito genes in each of these two fractions will be determined using microarray hybridization. This approach will not only provide more accurate information regarding the rate of protein synthesis, it also will lead to the discovery of general and gene-specific translational regulation in response to Plasmodium infection. The specific aims of this project are: 1) To discover translational regulations of mosquito genes in the midgut in response to Plasmodium infection. 2) To determine whether the translational regulations of midgut mRNA differ between the Plasmodium falciparum-susceptible and -refractory mosquitoes during Plasmodium infection. PUBLIC HEALTH RELEVANCE: Project Narrative The malaria parasites must undergo a series of developmental transformations inside the mosquito vector to become infectious to vertebrate hosts. We will use a new genome-wide approach to study protein synthesis in mosquitoes after ingestion of parasites with a blood meal. The results from this study will advance our knowledge of mosquito-malaria parasite interaction and reveal genetic factors that determine the ability of the mosquitoes to transmit the parasites. The new insights in turn may lead to new strategies for malaria control.

描述（由申请人提供）：疟疾是世界上最重要的热带寄生虫病。它造成了全球 2% 的死亡和非洲 9% 的死亡。超过 30 亿人生活在疟疾的威胁之下。不同蚊种的蚊子传播疟疾寄生虫的能力各不相同，甚至同一物种的不同地理品系之间也是如此。我们的长期目标是确定在蚊子对疟疾寄生虫疟原虫的易感性或耐药性方面发挥核心作用的蚊子基因，并利用这些知识来帮助未来控制疟疾传播的努力。了解寄生虫与载体相互作用的分子细节在很大程度上依赖于对疟原虫感染期间蚊子中新生蛋白质合成的精确测量。目前的表达谱主要监测 mRNA 稳态水平的变化。然而，由于各种转录后和翻译调节机制，转录组中每个给定 mRNA 的丰度不一定反映蛋白质组中编码蛋白质的表达。一些蚊子因子可能未被识别，因为在蚊子摄入疟原虫感染的血粉后，它们是通过翻译而不是转录调节的。该研究计划将 mRNA 分析与 mRNA 翻译状态的全基因组分析相结合，以同时监测蚊子转录组和新生蛋白质合成的变化。我们将使用蔗糖密度梯度离心将与多核糖体相关的 mRNA 与翻译失活的 mRNA 分开。这两个部分中各个蚊子基因的 mRNA 水平将使用微阵列杂交来确定。这种方法不仅将提供有关蛋白质合成速率的更准确信息，还将导致发现针对疟原虫感染的一般和基因特异性翻译调控。该项目的具体目标是：1）发现中肠中蚊子基因响应疟原虫感染的翻译调控。 2) 确定恶性疟原虫感染过程中易感蚊子和难治性蚊子的中肠mRNA翻译调控是否存在差异。公共卫生相关性：项目叙述 疟原虫必须在蚊媒体内经历一系列发育转变，才能对脊椎动物宿主具有感染性。我们将使用一种新的全基因组方法来研究蚊子通过血粉摄入寄生虫后的蛋白质合成。这项研究的结果将增进我们对蚊子与疟疾寄生虫相互作用的了解，并揭示决定蚊子传播寄生虫能力的遗传因素。新的见解反过来可能会带来控制疟疾的新策略。