Undine Gottesbuehren
Carolina Lage Crespo
Jaron Liu
Anna Lukacs
Giulia Morlino
Andrea Reboldi
Vinatha Sreeramkumar
›› Silvia Volpe
Maria Whitehead
Monika Wozinska
Silvia Volpe
Year of Birth: 1980
Citizenship: Italian
Host lab/direct supervisor: Institute for Research in Biomedicine(IRB)/Prof. Marcus Thelen

Undergraduate education: Study of Biological Sciences with focus on Biochemical Science. 21st October 2005 MSc in Biology at the University of L’Aquila (Italy), (Title: “The Effect of Cysteamine on Activity of Detoxifying and Antioxidative Enzymes in Vanin-1 Null-Mice).

Statement of research interests: Potential mechanisms of G-protein coupled receptor-mediated cell migration. The critical function of chemokines and their receptors in cell migration was first described in inflammatory reactions. Evidences accumulated over the years revealed that essentially all leukocyte trafficking during development, inflammation and homing is regulated by the chemokine system. In general, inflammatory chemokines attract leukocytes to sites of injury, whereas homeostatic chemokines recruit immune cells to lymphoid organs and mediate their development though multiple reactions between chemokines and their receptors. In addition chemokines can mediate cell migration during embryonic development and tumor metastasis. Cell migration is initiated by the binding of a chemokine (agonist) to a seven transmembrane domain receptor, also called G-protein coupled receptor (GPCR). Chemokine receptors share highly conserved domains, such as the DRYL/IAIV sequence at the N-terminus of the second intracellular loop and a CxNPxxY sequence in helix seven. Despite their structural similarity and the coupling to the same type of Gi-proteins, the chemokine receptors activate common and specific signal transduction pathways leading to diverse responses. A possible explanation for these observations is that GPCR can form oligomers which couple selectively to scaffolding molecules. In line with such view it was shown that chemokine receptors are present at the plasma membrane as homo- or heterodimers. The investigations shall focus on two aspects of chemokine receptor-mediated cell migration. 1) The spatio-temporal activation of G-protein coupled receptors in moving cells. How is the receptor activity controlled in polarized cells, which migrate through a shallow gradient of chemoattractant? Using receptors tagged with fluorescent probes it should be possible to monitor their activation states at different sites of a cell. Recently it was shown that intramolecular fluorescence resonance energy transfer (FRET) of GFP/YFP tagged GPCR reliably reports the activation state with kinetics comparable to wild type molecules. The FRET studies were performed with the Gi-coupled 2-adrenergic receptor (2AR). In the host laboratory critical preliminary experiments have been performed, which indicated that the 2AR can induce cell migration and the constructs may be used as a model to reveal the activation state of chemotaxis-mediating receptors. 2) Cell migration is accompanied by a profound remodeling of the actin cytoskeleton. Several lines of evidence indicate that RhoGTPases are critical upstream regulators of this process. While investigating chemokine receptor-mediated cell migration the host laboratory observed that the RhoGTPase specific GTP exchange factor P-Rex1 becomes rapidly and transiently phosphorylated. The kinetics of P-Rex1 phosphorylation are in agreement with the protein being involved in rapid Rho-GTPase activation and actin polymerization. Preliminary data suggest the presence of multiple phosphorylation sites which could affect activity and localization of the protein. My investigations shall disclose the physiological role of the different phosphorylation events and to delineate the pathways which lead to the posttranslational modifications. In addition, modified proteins will be generated to use FRET to investigate the involvement of P-Rex 1 in chemokine-receptor stimulated cell migration. The results may provide new insights on the regulation of leukocyte trafficking, a critical event during beneficial and malignant inflammatory responses. Comparison of chemokine-stimulated cell migration by different receptors and distinct cellular systems may eventually lead to biomarkers that are specific for some, but not all chemotactic pathways, and may be used to selectively interfere with cell trafficking.

Expectations from Integramm: I'm convinced, that the well supervised and individually tailored research and training program of the International Graduate Program in Molecular Medicine will provide me an excellent environment to perform my PhD work and the international setting of the Network of Excellence will be highly stimulating for my future career.