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Signal transduction in chronic inflammatory diseases

Tuesday 12 January 2016

Project
Inflammatory cytokines, cell-cell interactions, stress and danger signals contribute to altered cellular function by activating specific receptors and generating a cascade of intracellular signaling events, such as reversible phosphorylation or acetylation of additional signaling proteins or transcription factors. These signaling pathways interact with epigenetic regulatory proteins to cause aberrant gene expression and cellular function in many chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), systemic sclerosis (SSc), and lupus (SLE). In this project line, we cooperate with Prof. Dr. Tim Radstake and Dr. Joel van Roon, using gene expression studies to identify specific signaling cascades which are altered in individual white blood cell and stromal cell populations isolated from patients. We then use overexpression studies, gene silencing, and novel pharmacological compounds to modify the function of these epigenetic regulatory proteins and assess their effects on cellular function and gene expression. In the future, we will examine how the dynamic regulation of these specific signaling pathways contributes to or predicts patient responses to treatment in the clinic.

Techniques
Flow cytometry, RNA-seq, qPCR, immunoblotting, adenoviral expression, gene silencing, invasion assays, ELISA, tissue cell isolation, cell-cell interaction assays

Duration
6 or 9 months

Contact
Kris Reedquist, k.a.reedquist@umcutrecht.nl

References
1. Angiolilli C, Grabiec AM, Ferguson BS, Ospelt C, Malvar Fernandez B, van Es IE, van Baarsen LGM, Gay S, McKinsey TA, Tak PP, Baeten DL, Reedquist KA (2014). Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Ann Rheum Dis doi:10.1136/annrheumdis-2014-205635.
2. Hartkamp LM, Fine JS, van Es IE, Tang MW, Smith M, Woods J, Narula S, DeMartino J, Tak PP, Reedquist KA (2015). Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants. Ann Rheum Dis 74:1603-11.