MicroRNA regulation of Anopheles immunity to Plasmodium

 描述（由申请人提供）：疟疾由疟原虫寄生虫引起，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控制和消灭。迫切需要加深我们对病媒生物过程的了解，有可能利用这些生物过程来阻断疟疾传播。蚊子的先天免疫在疟原虫和蚊子媒介之间的相互作用中起着关键作用，并且是媒介能力的决定因素。在这项研究中，我们将鉴定蚊子用来调节其对疟原虫感染的防御的microRNAs（miRNAs），并确定操纵所选miRNAs的水平是否可以增强蚊子对疟原虫感染的抵抗力。miRNAs是一种内源性小分子RNA，在转录后调节基因表达。它们通过部分序列互补性识别其靶mRNA转录物。miRNA已被证明通过靶向参与相同生物过程的多个基因而充当主调节剂。我们的初步研究清楚地表明，miRNAs参与调节蚊子对疟原虫的防御反应。我们对miRNA-mRNA相互作用进行了全基因组分析，发现某些蚊子免疫基因的转录物在疟原虫感染后受到某些miRNAs的差异调节。我们将研究这些确定的miRNAs是否影响疟原虫寄生虫的生存，何时何地发生的调节，以及哪些基因在疟原虫动合子中肠入侵过程中受到miRNAs的调节（直接或间接）。本研究的具体目的是：（1）研究恶性疟原虫感染对中肠上皮细胞miRNA-mRNA相互作用的影响。gambiae，（2）选择在抗疟原虫防御中起重要调节作用的miRNA，和（3）使用miRNA或miRNA海绵的转基因表达来增强蚊子对疟原虫感染的抗性。我们提出的研究解决了在蚊子-疟原虫相互作用中理解miRNA功能的严重空白，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.