SFB854 TP-A01: Einfluss des Kälteschockproteins YB-1 auf den proinflammatorischen Mesangialphänotyp und die entzündliche Zellaktivierung

Bei entzündlichen Erkrankungen der Nierenkörperchen stimulieren Zytokine die Synthese und Freisetzung des Y-box Proteins-1 (YB-1). Ziel ist es, zugrunde liegende Regulationsmechanismen zu verstehen, die eine "Aktivierung" von YB-1 mit Proteinveränderungen, proteolytischer Spaltung und Freisetzung in vitro und in vivo bedingen. Die Effekte des freigesetzten YB-1 auf Mesangial-, Tubulus- und Entzündungszellen (T-Zellen, Monozyten) werden charakterisiert und nach Oberflächenrezeptoren gefahndet. Die funktionelle Bedeutung des extrazellulären YB-1 Proteins wird in Tiermodellen untersucht.

Influence of cold shock Y-box (YB) protein-1 on the proinflammatory mesangial cell phenotype and inflammatory cell activation

The orchestration of inflammatory reactions by the cold shock Y-box protein-1 (YB-1) and its role in the development of specific organ damage are investigated. In the kidney, a secreted form of YB-1 interacts with membrane-anchored receptors that initiate autoregulatory loops which enhance the expression of YB-1 in mesangial cells, alter gene transcription, and link intra- with extracellular activities. Our results demonstrate proteolysis and posttranslational modifications of intracellular YB-1 that are linked to inflammation. Acetylated YB-1 is secreted and YB-1-mediated receptor signaling enhances immune cell proliferation and chemotaxis. We hypothesize that YB-1 is centrally involved in the orchestration of immune responses and will elucidate the pathways leading to the processing of YB-1, characterize the subcellular distribution of YB-1 fragments, as well as the effects they mediate. The involvement of extracellular YB-1 in cell-cell communication will be determined with respect to receptor:ligand interaction(s) and downstream signaling pathways. Questions relating to misdirected and pathophysiological roles of extracellular YB-1, including autoantibody formation as well as YB-1-oligomerization in the context of (auto-) immune diseases will be addressed. In conditional YB-1fl/fl knockout and transgenic YB-1K299A/K302A knockin mice, with a suspected secretion deficiency, YB-1-dependent effects will be assessed in vivo in disease models.