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

这项建议的目的是了解受体信号转导的调节和生物学的基本原理。最近的证据表明，受体信号不仅发生在质膜上，而且还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中的一种调节原则。这项拟议的项目通过首次定义死亡受体内吞作用在生理环境中的作用，探索了受体信号转导中的新调节主题。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TNFR1的特异性内吞速率将通过小鼠敲击方法进行遗传改变。根据体外研究结果，我们假设Fas-或TNFR1受体内吞缺陷将导致突变小鼠从促凋亡信号转变为促炎症信号。通过促进“不想要的”潜在危险细胞的存活，这可能会产生严重的病理后果，并可能导致自身免疫和/或癌症的发展。因此，我们的研究不仅将为死亡受体生物学提供重要的新见解，而且还将揭示受体内吞作用和激活受体在活体中的亚细胞运输的生理学相关性。这些知识对我们理解免疫紊乱和癌症也是至关重要的，并可能为潜在的新诊断和治疗应用开辟新的前景。

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.