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

点击翻译按钮获取中文摘要

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.