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

对尿敏感的转录因子TonEBP/NFAT 5（张力响应性增强子结合蛋白/活化T细胞核因子5）在尿浓缩过程和肾髓质细胞的尿适应中起着中心作用。然而，最近的证据表明，各种病理学与局部渗透应激相关，并且TonEBP/NFAT 5在这些条件下被激活，这刺激各种促炎细胞因子的表达。初步研究表明TonEBP/NFAT 5和NF-κ B之间存在协同信号传导途径和分子相互作用。因此，了解调节TonEBP/NFAT 5活性的机制并解决TonEBP/NFAT 5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/NFAT 5的调节，并研究渗透应激增强炎症反应的机制。特别地，将解决TonEBP/NFAT 5和NF-κ B之间的假定分子相互作用。随后，将在LPS/脓毒症模型中的条件性TonEBP/NFAT 5敲除小鼠（在申请人的实验室中产生）中证实在细胞培养模型中获得的结果。这些实验和预期的数据是高度相关的，因为越来越多的证据表明，TonEBP/NFAT 5是NF-κ B激活和炎症反应所必需的，并且渗透压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.