Molecular Mechanisms and Signal-Induced Regulation of Alternative Splicing

选择性剪接的分子机制和信号诱导调控

基本信息

  • 批准号:
    10217584
  • 负责人:
  • 金额:
    $ 10.8万
  • 依托单位:
  • 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 2021-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary The ultimate goal of this project is to understand the molecular mechanisms by which RNA processing is controlled by signaling pathways, and the impact of this regulation on cellular function. The specific focus of the current funding period is on regulation of alternative pre-mRNA splicing during T cell activation. Alternative splicing is an essential and ubiquitous mechanism of gene regulation, which allows for the diversification and control of protein expression in distinct cell-types or environmental conditions. In particular, it is well established that signal-induced alternative splicing is pervasive during neuronal activity, nutrient sensing, oncogenesis and immune function. However, a mechanistic view of how signaling pathways control alternative splicing remains lacking. T cell activation provides an excellent a model system for complex cellular responses, in that multiple signaling pathways are triggered downstream of antigen engagement and act, individually and cooperatively, to induce T cell effector functions. Importantly, several hundred genes are known to undergo alternative splicing in response to T cell activation; however, it remains to be determined how these genes are regulated, which genes are co-regulated by overlapping mechanisms/pathways, and what the ultimate functional consequence is of such regulation. This proposal will address these unanswered questions of signal- induced alternative splicing by leveraging recently developed methodologies and systems to determine: (1) the specific signaling pathways that lead to changes in alternative splicing following antigen stimulation of T cells, and the RNA binding proteins (RBPs) that connect each signaling pathway with their respective splicing targets; (2) the molecular mechanisms by which RBPs and/or cell signaling regulate specific transitions in spliceosome assembly to direct isoform expression; (3) the functional impact of alternative splicing on cell signaling through regulating isoform expression of related kinases; and (4) how regulation of alternative splicing is coordinated with other RNA biogenesis events such as transcription and 3' end processing. Together these studies will provide novel insight regarding the interplay of signaling and splicing in shaping cellular function during T cell activation. Since the signaling pathways induced upon T cell activation are also functional in pathways related to cell growth, metabolism and cancer, the insight gained in these studies will be broadly applicable to numerous cellular responses far beyond the immune system. In addition, the studies proposed here will reveal new paradigms regarding the molecular mechanisms by which cells regulate spliceosome assembly, and how RBPs coordinately control splicing along with other steps in RNA processing. Results from these experiments will thus significantly increase understanding of the mechanisms that control alternative splicing, an essential and ubiquitous process for regulating gene expression across all human cell types.
项目摘要 这个项目的最终目标是了解RNA加工的分子机制 由信号通路控制,以及这种调节对细胞功能的影响。的具体焦点。 目前的资助期是关于在T细胞激活过程中对替代前mRNA剪接的调节。备择 剪接是一种基本的和普遍存在的基因调控机制,它允许基因的多样化和 控制蛋白质在不同细胞类型或环境条件下的表达。特别是,它是很好的 证实了信号诱导的选择性剪接在神经元活动、营养感知、 肿瘤发生和免疫功能。然而,一种关于信号通路如何控制替代选择的机械观点 拼接仍然缺乏。T细胞激活为复杂的细胞反应提供了一个极好的模型系统, 因为多条信号通路在抗原结合和作用的下游被触发,单独和 协同作用,诱导T细胞效应器功能。重要的是,已知的数百个基因经历了 应答T细胞激活的选择性剪接;然而,这些基因如何被确定仍有待确定 哪些基因受重叠的机制/途径共同调控,最终是什么? 功能后果就是这样的规则。这项建议将解决这些悬而未决的信号问题- 通过利用最近开发的方法和系统来确定:(1) T细胞抗原刺激后导致选择性剪接改变的特定信号通路, 以及将每条信号通路与各自的剪接连接起来的RNA结合蛋白(RBP) 靶点;(2)限制性商业惯例和/或细胞信号调节特定基因转换的分子机制。 剪接体组装直接异构体表达;(3)选择性剪接对细胞功能的影响 通过调节相关激酶的异构体表达来进行信号传递;以及(4)如何调节替代性 剪接与其他RNA生物发生事件相协调,如转录和3‘端加工。 总之,这些研究将为信号和剪接在塑造过程中的相互作用提供新的见解 T细胞活化过程中的细胞功能。由于诱导T细胞激活的信号通路也是 在与细胞生长、新陈代谢和癌症相关的通路中发挥作用,这些研究获得的洞察力将是 广泛适用于远远超出免疫系统的众多细胞反应。此外,这些研究 这将揭示关于细胞调节分子机制的新范式 剪接体组装,以及限制性商业惯例如何协调控制剪接与RNA加工中的其他步骤。 因此,这些实验的结果将显著增加对控制 选择性剪接--调节整个人类细胞中基因表达的一种基本且普遍的过程 类型。

项目成果

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KRISTEN W LYNCH其他文献

KRISTEN W LYNCH的其他文献

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{{ truncateString('KRISTEN W LYNCH', 18)}}的其他基金

High-Throughput Assay for Profiling Alternative Splicing and Splicing Regulators
用于分析选择性剪接和剪接调节器的高通量分析
  • 批准号:
    9797508
  • 财政年份:
    2019
  • 资助金额:
    $ 10.8万
  • 项目类别:
Signal-Induced Regulation of Alternative RNA Processing
替代 RNA 加工的信号诱导调节
  • 批准号:
    10598066
  • 财政年份:
    2016
  • 资助金额:
    $ 10.8万
  • 项目类别:
Signal-Induced Regulation of Alternative RNA Processing
替代 RNA 加工的信号诱导调节
  • 批准号:
    10400112
  • 财政年份:
    2016
  • 资助金额:
    $ 10.8万
  • 项目类别:
Molecular Mechanisms and Signal-Induced Regulation of Alternative Splicing
选择性剪接的分子机制和信号诱导调控
  • 批准号:
    9271211
  • 财政年份:
    2016
  • 资助金额:
    $ 10.8万
  • 项目类别:
Signal-Induced Regulation of Alternative RNA Processing
替代 RNA 加工的信号诱导调节
  • 批准号:
    10201033
  • 财政年份:
    2016
  • 资助金额:
    $ 10.8万
  • 项目类别:
Molecular Mechanisms and Signal-Induced Regulation of Alternative Splicing
选择性剪接的分子机制和信号诱导调控
  • 批准号:
    9913561
  • 财政年份:
    2016
  • 资助金额:
    $ 10.8万
  • 项目类别:
Mechanisms and consequences of CELF2 regulation in T cell development
T 细胞发育中 CELF2 调节的机制和后果
  • 批准号:
    8916790
  • 财政年份:
    2012
  • 资助金额:
    $ 10.8万
  • 项目类别:
Mechanisms and consequences of CELF2 regulation in T cell development
T 细胞发育中 CELF2 调节的机制和后果
  • 批准号:
    8525408
  • 财政年份:
    2012
  • 资助金额:
    $ 10.8万
  • 项目类别:
Mechanisms and consequences of CELF2 regulation in T cell development
T 细胞发育中 CELF2 调节的机制和后果
  • 批准号:
    8723862
  • 财政年份:
    2012
  • 资助金额:
    $ 10.8万
  • 项目类别:
Mechanisms and consequences of CELF2 regulation in T cell development
T 细胞发育中 CELF2 调节的机制和后果
  • 批准号:
    8410141
  • 财政年份:
    2012
  • 资助金额:
    $ 10.8万
  • 项目类别:

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Grin1 的选择性剪接控制生理和疾病过程中的 NMDA 受体功能
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CAREER: Mechanotransduction, transcription, and alternative splicing in cell biology
职业:细胞生物学中的机械转导、转录和选择性剪接
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