Regulation and synergistic interaction of the transcription factor TonEBP/NFAT5 with NF-kappaB: Osmotic stress as proinflammatory signal

渗透敏感转录因子TonEBP/NFAT5（强直反应增强子结合蛋白/活化T细胞的核因子5）在尿浓缩过程和肾髓细胞的渗透适应中都起着核心作用。然而，最近的证据表明，各种病理与局部渗透应激有关，TonEBP/NFAT5在这些条件下被激活，从而刺激各种促炎细胞因子的表达。初步研究表明TonEBP/NFAT5和NF-kappaB之间存在协同信号通路和分子相互作用。因此，了解调节TonEBP/NFAT5活性的机制，并解决TonEBP/NFAT5在肾外组织和病理生理条件下的作用至关重要。在计划的项目中，将在细胞培养实验中研究TonEBP/NFAT5的调控，并研究渗透应激增强炎症反应的机制。特别地，TonEBP/NFAT5和NF-kappaB之间假定的分子相互作用将被讨论。随后，在细胞培养模型中获得的结果将在条件TonEBP/NFAT5敲除小鼠（在申请人实验室中产生）的LPS/脓毒症模型中得到证实。这些实验和预期的数据高度相关，因为越来越多的证据表明，TonEBP/NFAT5是NF-kappaB激活和炎症反应所必需的，而渗透应激进一步增强了这一过程。

The osmosensitive transcription factor TonEBP/NFAT5 (tonicity-responsive enhancer binding protein/nuclear factor of activated T cells 5) plays a central role both for the urinary concentating process and for the osmoadaptation of renal medullary cells. Recent evidence suggests however that various pathologies are associated with local osmotic stress and that TonEBP/NFAT5 is activated under these conditions, which stimulates the expression of various proinflammatory cytokines. Preliminary studies indicate synergistic signalling pathways and molecular interactions between TonEBP/NFAT5 und NF-kappaB. Therefore, it is of central importance to understand the mechanisms that regulate TonEBP/NFAT5 activity and to address the role of TonEBP/NFAT5 in extrarenal tissues and under pathophysiological conditions. In the planned projects, the regulation of TonEBP/NFAT5 will be investigated in cell culture experiments and the mechanism, by which osmotic stress enhances inflammatory responses, will be investigated. Particularly, a putative molecular interaction between TonEBP/NFAT5 and NF-kappaB will be addressed. Subsequently, the results obtained in cell culture models will be confirmed in conditional TonEBP/NFAT5 knockout mice (generated in the applicants' lab) in a LPS/sepsis model. These experiments and the expected data are highly relevant since increasing evidence suggests that TonEBP/NFAT5 is required for NF-kappaB activation and inflammatory responses and that osmotic stress further enhances this process.