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Stress signaling mechanisms in metabolism and inflammation and related disorders (STRESSMETABOL)
Start date: Feb 1, 2012, End date: Jan 31, 2017 PROJECT  FINISHED 

"Protein kinases represent key signal transduction components transferring signals to their effectors by phosphorylation. Among other important functions, MAPK-dependent signal transduction is principally required to control inflammation and metabolism in vertebrates. However, chronic MAPK signaling in response to environmental stress contributes to the development of metabolic and inflammatory diseases.While most studies investigated functions of p38α of the p38 MAPK family, we have recently identified first non-redundant in vivo functions for p38δ. We found that p38δ regulates glucose homeostasis by controlling insulin secretion from pancreatic β cells and more recently that p38δ is pivotal in regulation of neutrophil-mediated inflammation. At the molecular level, both functions are dependent on Protein Kinase D1 (PKD1) activity, the latter of which, we identified as a direct and negatively regulated target of p38δ. Overall, our recent work describes a new signaling axis that may be important in diabetes mellitus and inflammatory diseases, respectively.The future core activity of my laboratory is directed towards elucidation of particular roles of p38δ and PKD1 downstream targets in neutrophils and β cells. We also aim at finding common upstream signaling mechanisms that converge in p38δ-PKD1 signaling. Finally, we will explore newly discovered potential metabolic processes that are regulated by this signaling module. This biased research will be complemented by a more comprehensive proteomic screening approach in liver focusing on basic metabolic adaption in response to fasting and feeding. While, protein phosphorylation is widely explored in this context, we will globally screen for ubiquitination of proteins that recently emerged as a key event in cellular signaling.Our work will hopefully lead to the discovery of novel and important cellular and molecular mechanisms in metabolism and inflammation with relevant implications in related human disorders."

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