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Signal-Induced Regulation of Alternative RNA Processing

替代 RNA 加工的信号诱导调节

基本信息

批准号：
10598066
负责人：
KRISTEN W LYNCH
金额：
$ 60.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2016-05-09 至 2026-04-30
项目状态：
未结题

项目摘要

Project Summary The ultimate goal of this project is to understand the interplay of cell signaling and RNA processing in shaping cellular gene expression and function. The specific focus of the current funding period is in unraveling the regulatory connections that exist between signaling pathways and RNA processing events, and the RNA binding proteins (RBPs) that maintain these connections. Decades of work have revealed that cell signaling pathways are central to controlling cellular function in response to environmental cues. Similarly, all of the steps of RNA processing, including alternative splicing, alternative polyadenylation and regulated mRNA stability, can be regulated to dictate the identity or abundance of the final mRNA and proteins. Historically, most work on the impact of cell signaling on gene expression has focused on the regulation of transcription. Therefore, how cell signaling impinges on the various mechanisms of RNA processing, and conversely, how RNA processing shapes the cellular response to environmental challenges, remain largely unexplored areas of research that are critical to our broad understanding of cellular activity. T cell activation provides an excellent a model system for complex cellular responses, as multiple signaling pathways are triggered downstream of antigen engagement and act, individually and cooperatively, to induce T cell effector functions. It has been well documented that T cell activation leads to changes in alternative splicing, polyadenylation and mRNA stability. Moreover, changes in these RNA processing events impact additional signaling pathway such as apoptosis and inflammation, which are critical secondary responses to T cell activation. However, many questions regarding the regulatory connections between RNA processing and signaling remain, including identifying the RBPs that link signaling to RNA processing, understanding the functional impact of processing events triggered by one signal on other pathways, and determining how individual RBPs coordinate multiple steps of RNA processing. This proposal will address these unanswered questions of signal-induced RNA processing by leveraging recent results and systems to determine how alternative splicing controls apoptosis and interferon responsive signaling in activated T cells, the proteins that control alternative polyadenylation and mRNA stability in response to T cell signaling, and a potential new mechanism for the regulation of translation by the RBP CELF2. Together these studies will provide novel insight regarding the interplay of signaling and RNA processing in shaping cellular function during T cell activation. Since the signaling pathways studied here are related to cell growth and death, the insight gained in these studies will be broadly applicable far beyond T cell biology. In addition, these studies will reveal new paradigms regarding the molecular mechanisms by which RBPs coordinately control multiple steps in RNA processing. Thus, results from these experiments will significantly increase the general understanding of the mechanisms that control proteome expression and cellular function in response to environmental cues.

项目摘要这个项目的最终目标是了解细胞信号和RNA处理在成形过程中的相互作用。细胞基因的表达和功能。当前供资期间的具体重点是解开存在于信号通路和RNA加工事件之间的调节连接，以及RNA 维持这些连接的结合蛋白(RBP)。数十年的研究表明，细胞信号通路是控制细胞功能以响应环境提示的中心。同样，所有的 RNA加工的步骤，包括选择性剪接、选择性聚腺苷酸化和受调控的mRNA 稳定性，可以调节以决定最终的信使核糖核酸和蛋白质的特性或丰度。从历史上看，大多数关于细胞信号对基因表达的影响的工作都集中在转录调控上。因此，细胞信号如何影响RNA加工的各种机制，反过来，又是如何 RNA处理塑造细胞对环境挑战的反应，在很大程度上仍然是尚未探索的领域对我们广泛了解细胞活动至关重要的研究。T细胞活化提供了一种极好的复杂细胞反应的模型系统，因为多个信号通路在下游被触发抗原结合，单独和协同作用，诱导T细胞效应器功能。一切都很好研究证明，T细胞的激活会导致选择性剪接、多聚腺苷酸化和mRNA稳定性的变化。此外，这些RNA加工事件的变化会影响额外的信号通路，如细胞凋亡以及炎症，这是对T细胞激活的关键次级反应。然而，许多问题关于RNA处理和信号之间的调节联系仍然存在，包括识别将信令与RNA处理联系起来的限制性商业惯例，了解处理事件的功能影响由其他路径上的一个信号触发，并确定单个RBP如何协调以下多个步骤 RNA处理。这项提案将通过以下方式解决这些尚未回答的信号诱导RNA处理问题利用最新结果和系统确定替代剪接如何控制细胞凋亡和干扰素激活的T细胞中的反应信号--控制交替多聚腺苷化和mRNA的蛋白质对T细胞信号的响应的稳定性，以及一种潜在的新的机制来调节翻译 RBP CELF2.总之，这些研究将为信号和RNA的相互作用提供新的见解在T细胞激活过程中塑造细胞功能的过程。因为这里研究的信号通路是与细胞生长和死亡有关，这些研究中获得的见解将广泛适用于T细胞以外的领域生物学。此外，这些研究将揭示关于分子机制的新范式限制性商业惯例协调控制RNA加工中的多个步骤。因此，这些实验的结果将显著提高了对控制蛋白质组表达和细胞对环境提示作出反应的功能。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing.

HNRNP K和NS1-BP在流感和人mRNA剪接中的共调节活性。

DOI：
10.1038/s41467-018-04779-4
发表时间：
2018-06-19
期刊：
Nature communications
影响因子：
16.6
作者：
Thompson MG;Muñoz-Moreno R;Bhat P;Roytenberg R;Lindberg J;Gazzara MR;Mallory MJ;Zhang K;García-Sastre A;Fontoura BMA;Lynch KW
通讯作者：
Lynch KW

Functional and Mechanistic Interplay of Host and Viral Alternative Splicing Regulation during Influenza Infection.