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Modeling of the TNF - TNF receptor signaling network

TNF - TNF 受体信号网络的建模

基本信息

批准号：
97175222
负责人：
Professor Dr. Thomas Dandekar
金额：
--
依托单位：
Abteilung für Molekulare Innere Medizin
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 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/97175222?language=en
关键词：
Modeling TNF receptor signaling network

项目摘要

Tumor necrosis factor (TNF) receptor-1 (TNFR1) and TNFR2 coexpressing cells with the potential to produce TNF, e.g. T-cells, macrophages, dendritic cells and fibroblasts, are of great importance for homeostasis of the immune system in general and have an overwhelming role in many autoimmune diseases. We and others have shown that the activity of signaling pathways engaged by TNFR1 and TNFR2 as well as the production of their stimulating ligands (TNFR1: soluble and membrane TNF, TNFR2: membrane TNF) are integrated by a variety of connected positive and negative feedback loops. The quality (inflammation versus apoptosis), duration and amplitude of the cellular TNF response are therefore currently not predictable. The rational development and refinement of therapy concepts relying on interference with the function of the TNF-TNF receptor system are therefore not feasible yet and instead base to considerable extent on “trial and error”. It is the aim of this project to develop a mathematical model describing TNF-induced cellular responses of TNFR1 and TNFR2 coexpressing TNF producing cells under special consideration of the regulatory principles revealed in our previous work. The modeling work will be accompanied by experimental work to verify the predictive power of the model and yet not available crucial biochemical parameters of relevance for the modeling approach will be determined.

肿瘤坏死因子（TNF）受体-1（TNFR 1）和TNFR 2共表达细胞具有产生TNF的潜力，例如T细胞、巨噬细胞、树突细胞和成纤维细胞，通常对于免疫系统的稳态非常重要，并且在许多自身免疫性疾病中具有压倒性的作用。我们和其他人已经表明，由TNFR 1和TNFR 2参与的信号通路的活性以及它们的刺激配体（TNFR 1：可溶性和膜TNF，TNFR 2：膜TNF）的产生通过各种连接的正反馈和负反馈回路来整合。因此，目前无法预测细胞TNF应答的质量（炎症与凋亡）、持续时间和幅度。因此，依赖于干扰TNF-TNF受体系统的功能的治疗概念的合理开发和完善还不可行，而是在相当大的程度上基于“试错法”。这是本项目的目的是开发一个数学模型，描述TNF诱导的细胞反应的TNFR 1和TNFR 2共表达TNF生产细胞的调节原则，在我们以前的工作中揭示的特别考虑。建模工作将伴随着实验工作，以验证模型的预测能力，但尚未确定与建模方法相关的关键生化参数。