MicroRNA regulation of Anopheles immunity to Plasmodium

 描述(申请人提供)：疟疾由疟原虫引起，并通过雌性按蚊传播给人类。目前的疟疾控制措施可能不足以实现有效的控制和消除。迫切需要促进我们对媒介生物过程的了解，这些过程可能被用来努力阻止疟疾的传播。蚊子的先天免疫在疟疾寄生虫与蚊媒的相互作用中起着关键作用，是媒介能力的决定因素。在这项研究中，我们将确定蚊子用来调节其对疟疾感染的防御的microRNAs(MiRNAs)，并将确定操纵选定的miRNAs的水平是否可以增强蚊子对疟疾感染的抵抗力。MiRNAs是一种小的内源性RNA分子，在转录后调节基因表达。它们通过部分序列互补来识别他们的目标mRNA转录本。已有研究表明，miRNAs通过靶向同一生物过程中涉及的多个基因而发挥主要调节作用。我们的初步研究清楚地表明，miRNAs参与调节蚊子对疟疾寄生虫的防御反应。我们已经对miRNA-mRNA相互作用进行了全基因组分析，并发现一些蚊子免疫基因的转录产物受到某些miRNAs的差异调控，以响应疟原虫的感染。我们将研究这些已识别的miRNAs是否影响疟原虫的生存，何时何地发生调控，以及在动型疟原虫入侵中肠期间，哪些基因受到miRNAs的(直接或间接)调控。本项目的具体目的是：(1)鉴定恶性疟原虫感染对AN中肠上皮细胞miRNA-mRNA相互作用的影响。(2)选择在抗疟原虫防御中发挥重要调节作用的miRNAs，以及(3)利用miRNAs或miRNA海绵的转基因表达来增强蚊子对疟原虫感染的抵抗力。我们提出的研究解决了在蚊子和疟原虫相互作用中miRNA功能的一个严重空白，并可能为阻断疟疾传播提供新的分子靶点。

 DESCRIPTION (provided by applicant): Malaria is caused by Plasmodium parasites and is transmitted to humans by female Anopheles mosquitoes. Current malaria control measures may not be sufficient to achieve effective control and elimination. There is an urgent need to advance our understanding of the vector's biological processes that can potentially be exploited in an effort to block malaria transmission. The mosquito's innate immunity plays a pivotal role in the interaction between the malaria parasites and the mosquito vector, and is a determining factor of vectorial capacity. In this study, we will identify microRNAs (miRNAs) used by mosquitoes to modulate their defense against Plasmodium infection and will determine whether manipulating the levels of the selected miRNAs can lead to enhanced mosquito resistance to Plasmodium infection. miRNAs are small endogenous RNA molecules that post-transcriptionally regulate gene expression. They recognize their target mRNA transcripts through partial sequence complementarity. miRNAs have been shown to act as master regulators by targeting multiple genes involved in the same biological process. Our preliminary studies clearly demonstrate that miRNAs are involved in modulating the mosquito defense response to malaria parasites. We have performed a genome-wide analysis of miRNA-mRNA interactions and discovered that the transcripts of some mosquito immune genes are differentially regulated by certain miRNAs in response to Plasmodium infection. We will investigate whether these identified miRNAs affect the survival of Plasmodium parasites, when and where the regulation takes place, and which genes are regulated (directly or indirectly) by the miRNAs during midgut invasion by Plasmodium ookinetes. The specific aims of this project are to: (1) Identify miRNA-mRNA interactions affected by P. falciparum infection of the midgut epithelium in An. gambiae, (2) Select miRNAs that play important regulatory roles in anti-Plasmodium defense, and (3) Use transgenic expression of miRNAs or miRNA sponges to enhance mosquito resistance to Plasmodium infection. Our proposed study addresses a serious gap in the understanding of miRNA function in mosquito- Plasmodium interactions, and may provide novel molecular targets for blocking malaria transmission.