Functional analysis of regulated mRNA 3'end processing in the control of inflammatory processes, innate immunity and tumorigenesis

调节 mRNA 3 末端加工在控制炎症过程、先天免疫和肿瘤发生中的功能分析

• 批准号: 154974057
• 负责人: Professor Dr. Sven Danckwardt
• 金额: --
• 依托单位: Centrum für Thrombose und Hämostase (CTH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/154974057?language=en
• 关键词: Functional; analysis; regulated; mRNA; end

Posttranscriptional mechanisms that control gene expression play an increasingly recognized role in health and disease1-6. While substantial progress has been made to characterize many of these mechanisms, the regulation of mRNA 3’end processing is still poorly understood. Importantly, alternative and regulated mRNA 3’end processing modulates the expression of many genes7,8, often in response to extracellular stimuli6,8-10. Despite these findings, the involved signal-transduction pathways and their role to execute specific cellular programs are unknown. I will integrate bioinformatical, biochemical and functional genomic approaches to dissect the molecular and cellular mechanisms of regulated mRNA 3’end processing. We will identify functionally relevant factors and signaling pathways that modulate this step of mRNA processing in response to external stimuli. Furthermore, we will explore whether a novel class of transcripts, in which 3’end processing is activated by specific sequence elements6,11-19, represents a functionally coupled RNA operon to execute cellular programs in response to external stimuli20,21. Interestingly, this class includes many transcripts with key roles in inflammation and tumorigenesis. These findings will be translated into disease models that could ultimately provide novel insights into in vivo-validated targets and/or signaling components for therapeutic intervention.

控制基因表达的转录后机制在健康和疾病中起着越来越认可的作用1-6。尽管已经取得了实质性的进展来表征许多此类机制，但mRNA 3'End处理的调节仍然很少了解。重要的是，替代和调节的mRNA 3'端处理调节了许多基因7,8的表达，通常是针对细胞外刺激6,8-10的。尽管有这些发现，但涉及的信号转移途径及其执行特定蜂窝程序的作用尚不清楚。我将整合生物信息学，生化和功能基因组方法，以剖析受调节的mRNA 3'End加工的分子和细胞机制。我们将确定与功能相关的因素和信号通路，这些因素和信号通路可根据外部刺激调节mRNA处理的这一步骤。此外，我们将探讨一类新的转录本（其中3'端处理被特定序列元素激活6,11-19）是否代表了一部功能耦合的RNA Operaon来响应外部刺激20,21，以执行蜂窝程序。有趣的是，该类别包括许多在炎症和肿瘤发生中具有关键作用的转录本。这些发现将转化为疾病模型，这些模型最终可以为治疗干预的体内验证靶标和/或信号传导成分提供新的见解。