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The role of CXCL4 chemokine in the pathogenesis of autoimmune disease Systemic sclerosis

Tuesday 7 April 2015

The role of CXCL4 chemokine in the pathogenesis of autoimmune disease Systemic sclerosis
Dr. Wioleta Marut/Prof. Timothy Radstake

Project
Systemic sclerosis (SSc) is a disfiguring disease with high mortality and morbidity, characterized by progressive and uncontrollable fibrosis of the skin and internal organs.
Although the downstream pathways that lead to fibrosis remain obscure, our group recently demonstrated that plasmacytoid dendritic cells (pDC) play a primary role in driving fibrosis in SSc. We have demonstrated that these cells are highly activated in SSc and produce high levels of the chemokine CXCL4.
Moreover, our recent data suggest that CXCL4 can directly promote the fibrotic process, by transition of fully differentiated epithelial and endothelial cells into activated myofibroblasts, a process called epithelial/endothelial mesenchymal transition (EMT/EndoMT). Further, we found that CXCL4 increases ROS production in fibroblasts, which additionally stimulate synthesis and deposition of extracellular matrix (ECM) and can promote fibrosis. In accordance with high level of CXCL4 in the circulation and skin of SSc patients, it is important to further investigate mechanisms in which CXCL4 could contribute to SSc phenotype.

The main research goals are:
A) The mechanism responsible for EMT and EndoMT by CXCL4.
B) The role of CXCL4 in fibroblasts activation.
C) Investigate the role of ROS in fibrogenesis induced by CXCL4.

Techniques
Cell biological and molecular techniques such as: Flow cytometry, Western blotting, luminex, cell culture, qPCR, ROS measurments.

Duration
6 - 9 months

Contact
Dr. W.Marut, Email: w.k.marut@umcutrecht.nl, tel +31 (0)88 755 3568