Novel regulatory themes in immune cell signal transduction: Physiological functions of death receptor endocytosis

免疫细胞信号转导的新调控主题：死亡受体内吞作用的生理功能

• 批准号: 216342171
• 负责人: Professorin Dr. Kyeong-Hee Lee
• 金额: --
• 依托单位: Institut für Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/216342171?language=en
• 关键词: Novel; regulatory; themes; immune; cell

The objective of this proposal is to understand fundamental principals in the regulation and biology of receptor signal transduction. Recent evidence suggests that receptor signaling occurs not only at the plasma membrane, but also at specific endosomal compartments and receptor endocytosis is just beginning to emerge as a regulatory principle in receptor signal transduction. The proposed project explores novel regulatory themes in receptor signal transduction, by defining, for the first time, the role of death receptor endocytosis in a physiological context. To this end, novel and unique in vivo mouse model systems will be developed, in which the specific endocytosis rates of the death receptors Fas or TNFR1 will be genetically altered in a mouse knock-in approach. Based on in vitro findings, we hypothesize that defects in Fas- or TNFR1 receptor endocytosis will result in a shift from pro-apoptotic to pro-inflammatory signaling in mutant mice. By promoting the survival of ‘unwanted’, potentially dangerous cells, this may have severe pathological consequences and may lead to the development of autoimmunity and/or cancer. Thus our studies will not only provide important new insights into death receptor biology, but will also reveal the physiological relevance of receptor endocytosis and the subcellular trafficking of activated receptors in living organisms. Such knowledge is also critical for our understanding of immune disorders and cancer and may open up new prospects for potential new diagnostic and therapeutic applications.

本课程的目的是了解受体信号转导的调控和生物学的基本原理。最近的证据表明，受体信号转导不仅发生在质膜上，而且发生在特定的内体隔室，受体内吞作用刚刚开始成为受体信号转导的调节原则。拟议的项目探索新的受体信号转导的监管主题，通过定义，为第一次，在生理背景下死亡受体内吞作用的作用。为此，将开发新的和独特的体内小鼠模型系统，其中死亡受体Fas或TNFR 1的特异性内吞速率将在小鼠敲入方法中遗传改变。基于体外研究结果，我们假设Fas或TNFR 1受体内吞作用的缺陷将导致突变小鼠中促凋亡信号向促炎信号的转变。通过促进“不需要的”、潜在危险的细胞的存活，这可能具有严重的病理后果，并可能导致自身免疫和/或癌症的发展。因此，我们的研究不仅将提供重要的新见解死亡受体生物学，但也将揭示受体内吞作用和活化受体在活生物体中的亚细胞运输的生理相关性。这些知识对于我们理解免疫疾病和癌症也至关重要，并可能为潜在的新诊断和治疗应用开辟新的前景。