Synergism between IFNß and TNFa: non-canonical functions of STAT2 and IRF9 transcription factors

IFNα 和 TNFa 之间的协同作用：STAT2 和 IRF9 转录因子的非典型功能

• 批准号: RGPIN-2018-04279
• 负责人: Grandvaux, Nathalie
• 金额: $ 4.23万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=652316
• 关键词: Synergism; between; IFN; TNFa; non

Virtually all cell types secrete cytokines, key soluble mediators, to transmit signal of danger to activate an appropriate biological response. Cytokines act via cell surface receptors to elicit specific intracellular messages, known as signaling cascades, which ultimately transfer the message to the genome through the induction of a specific set genes to define an appropriate response. The molecular mechanisms that explain how a specific cytokine triggers a specific molecular pathway are the focus of numerous studies. Most studies aimed at describing the signaling cascades and biological outcome of cytokines are performed in simplified models using single cytokine stimulation. However, in a physiological situation it is highly unlikely that a cell is stimulated by one cytokine at a time as in a particular situation multiple cytokines are produced simultaneously. As a consequence, a cell rather responds to a cocktail of cytokines to foster an appropriate gene expression response. Our group is working to describe the signaling mechanisms that occurs when cells are stimulated with two cytokines, Interferon β and TNFα. Elevated levels of both cytokines are notably induced upon pathogen detection or in inflammatory conditions. Our work in progress strongly supports the existence of previously uncharacterized signaling cascades induced by the Interferon β and TNFα when used simultaneously. These novel signaling cascades are associated with the specific gene expression responses. The ultimate goal of this research program is to decipher the molecular mechanisms by which cells specifically respond in a coordinated fashion to IFNβ+TNFα. In addition to providing key cell biology understanding of situations with elevated IFNβ+TNFα, this research program will highlight novel paradigms that will translate to stimulation by other combination of cytokines. Biochemistry, molecular and cellular biology and bioinformatics analyses are required to solve the complexity and dynamics of the signaling cascades. We are in a privileged position to contribute significantly on a long-term basis to the discovery of these novel basics molecular mechanisms that control cell function. Undergraduate and graduate students participating to this program will gain a diversified training in biochemistry and molecular and cellular biology.

几乎所有类型的细胞都会分泌细胞因子，这是一种关键的可溶性介质，可以传递危险信号以激活适当的生物反应。细胞因子通过细胞表面受体产生特定的细胞内信息，称为信号级联反应，最终通过诱导一组特定的基因将信息传递给基因组，以确定适当的反应。解释特定细胞因子如何触发特定分子途径的分子机制是许多研究的焦点。大多数旨在描述细胞因子的信号级联和生物学结果的研究都是在使用单一细胞因子刺激的简化模型中进行的。然而，在生理情况下，细胞不太可能一次受到一种细胞因子的刺激，因为在特定情况下，多种细胞因子同时产生。因此，细胞会对细胞因子的混合物做出反应，以促进适当的基因表达反应。我们的团队正在努力描述当细胞受到干扰素β和TNFα两种细胞因子刺激时发生的信号传导机制。两种细胞因子的升高水平在病原体检测或炎症条件下明显诱导。我们正在进行的工作有力地支持了干扰素β和TNFα同时使用时诱导的先前未表征的信号级联的存在。这些新的信号级联反应与特定的基因表达反应有关。这项研究计划的最终目标是破译细胞以协调方式特异性响应IFNβ+TNFα的分子机制。除了对IFNβ+TNFα升高的情况提供关键的细胞生物学理解外，该研究项目还将强调将转化为其他细胞因子组合刺激的新范例。需要生物化学、分子和细胞生物学以及生物信息学分析来解决信号级联的复杂性和动态性。我们处于一个特殊的位置，可以在长期的基础上为发现这些控制细胞功能的新的基本分子机制做出重大贡献。参加本课程的本科生和研究生将在生物化学和分子与细胞生物学方面获得多样化的训练。