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: $ 8.45万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744378
• 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 and TNF. 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 and TNF 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 IFN+TNF. In addition to providing key cell biology understanding of situations with elevated IFN+TNF, 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.

几乎所有的细胞类型都分泌细胞因子，关键的可溶性介质，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发挥作用，引发特定的细胞内信息，称为信号级联，其最终通过诱导特定的一组基因将信息传递到基因组，以定义适当的反应。解释特定细胞因子如何触发特定分子途径的分子机制是众多研究的焦点。大多数旨在描述细胞因子的信号传导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，细胞一次被一种细胞因子刺激是极不可能的，因为在特定情况下同时产生多种细胞因子。因此，细胞更倾向于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。我们的小组正在努力描述当细胞被两种细胞因子干扰素和TNF刺激时发生的信号传导机制。两种细胞因子的水平升高在病原体检测时或在炎性病症中被显著诱导。我们正在进行的工作有力地支持了干扰素和TNF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对IFN+TNF特异性反应的分子机制。除了提供对IFN+TNF升高情况的关键细胞生物学理解外，该研究计划还将突出将转化为其他细胞因子组合刺激的新范式。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地位，可以长期为发现这些控制细胞功能的新的基础分子机制做出重大贡献。参加该计划的本科生和研究生将获得生物化学，分子和细胞生物学的多元化培训。