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Mechanisms Governing Translational Regulation During Plasmodium Transmission

疟原虫传播过程中翻译调控的机制

基本信息

批准号：
10667735
负责人：
Scott E Lindner
金额：
$ 47.75万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667735
关键词：
Address Adopted Affinity Anopheles Genus Back Bite Cues Culicidae Development Disease Electron Microscopy Essential Genes Face Failure Female Flow Cytometry Funding Gene Deletion Gene Expression Genes Genetic Transcription Image Immunologics In Situ Individual Investigation Link Liver Malaria Mango - dietary Messenger RNA Methods Midgut Oocysts Parasite Control Parasites Persons Phenotype Plasmodium Play Polyribosomes Preparation Process Protein Biochemistry Proteins Proteomics RNA RNA-Binding Proteins Regulation Repression Ribosomes Role Salivary Glands Skin Sporozoites Stimulus Structure Translating Translational Regulation Translational Repression Translations Work aptamer cryogenics design experimental study global health innovation malaria infection programs reconstruction response reverse genetics three dimensional structure transcriptomics transmission process vector

项目摘要

Project Summary New malarial infections start with a bite of a female Anopheles mosquito, which introduces the sporozoite form of the Plasmodium parasite into the skin of that individual. To get to this point, the parasite must have successfully infected and developed within the mosquito over the course of two weeks or more, using active responses to overcome the mosquito’s defenses. Having accomplished this, the sporozoite must now switch into a mode of preparation and become poised for a moment of opportunity to transmit from the mosquito back to its mammalian host. In this proposed work, we will identify key mechanisms by which the sporozoite can prepare itself through the translational regulation of selected mRNAs. Recently, it was discovered that sporozoites use two overlapping and orthogonal programs of translational repression (Programs 1 and 2) to allow translation of specific mRNAs to occur only at key moments in their development. However, while we now know many specific mRNAs that are regulated by these programs, we do not know what proteins act upon them to cause them to be silenced/repressed (trans factors). Moreover, while we know when these programs are turned off during development and transmission of the parasite, we do not know what environmental cues initiate this transition in translational regulation. Therefore, in this proposed work we will investigate the protein trans factors that allow for selective regulation of mRNAs that are known to be critical to sporozoite development and transmission. Through this work, we will identify the consequences of interfering with these regulatory programs, the environmental stimuli that are sensed to trigger the release of translational repression, and the central role that the specialized ribosome plays in these processes. These experimental questions will be addressed through reverse genetics, protein biochemistry, imaging flow cytometry, transcriptomics, proteomics, and cryogenic electron microscopy (cryo EM). In accomplishing this, we aim to identify crucial regulatory features of the malaria parasite that control sporozoite development and transmission to a new mammalian host.

项目摘要新的疟疾感染始于雌性按蚊的叮咬，这导致了子孢子的形式。将疟原虫的一部分带入个体皮肤。要做到这一点，寄生虫必须有在两周或更长时间内成功感染蚊子并在体内发育，使用Active 以克服蚊子的防御反应。完成这一任务后，子孢子现在必须转换进入准备模式，准备好等待从蚊子身上传回的机会给它的哺乳动物宿主。在这项拟议的工作中，我们将确定子孢子通过哪些关键机制通过对选定的mRNAs的翻译调节来为自己做准备。最近发现，子孢子利用两个相互重叠和正交的翻译程序。抑制(程序1和2)，以允许特定mRNA的翻译仅在其发展。然而，尽管我们现在知道许多受这些程序调控的特定mRNAs，但我们不知道是什么蛋白质作用于它们，导致它们沉默/抑制(反式因子)。此外，虽然我们知道这些程序在寄生虫的发展和传播过程中何时被关闭，但我们不知道是什么环境因素引发了转化性监管的这种转变。因此，在这项拟议的工作中，我们将研究允许选择性调节的蛋白质反式因子。已知对子孢子发育和传播至关重要的mRNAs。通过这项工作，我们将确定干扰这些监管计划的后果，环境刺激是感受到触发翻译抑制的释放，以及专门化核糖体的核心作用在这些过程中发挥作用。这些实验问题将通过反向遗传学、蛋白质生物化学、成像流式细胞术、转录组学、蛋白质组学和低温电子显微镜(低温电子显微镜 EM)。在实现这一点的过程中，我们的目标是确定控制疟疾寄生虫的关键调控特征子孢子发育和传播到新的哺乳动物宿主。