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Regulation of toll like receptor expression through the haematopoietic GTPase RhoH

The focus of the group of Dr Kubatzky is the transduction of cytokine-induced signalling events and the interaction of these classical pathways with those activated by bacterial toxins such as JAK-STAT, SOCS, heterotrimeric G-Proteins and small GTPases of the Rho family.

Rho GTPases play a central role in a variety of processes such as adhesion, motility, proliferation, differentiation and gene transcription. RhoH is a haematopoiesis specific, GTPase deficient member of the family of Rho GTPases whose function and regulation is not well understood. The protein was first discovered as a fusion transcript in Non Hodgkin lymphoma cells. In primary lymphoma cells RhoH is mutated with high frequency through somatic hypermutation. Alteration of RhoH expression levels can result in subnormal growth and function of cells so that implications for normal and malignant haematopoiesis can be expected. RhoH is known to be essential for the selection and maturation of thymocytes.  We were able to show that RhoH also acts as a regulator of STAT activity. Recent data suggest that RhoH may play a central role in regulation of differentiation versus proliferation events in cells of the immune system.

Recent studies in our lab gave evidence that the expression level of RhoH may influence the expression pattern of toll like receptors (TLRs) in a human T cell line. We plan to investigate the mechanism of this regulation by characterizing the activity of the signalling molecules involved and their interactions on a molecular level. We will further study the consequence of these RhoH dependent changes in signal transduction for the activity of TLRs and their ability to stimulate an appropriate immune response. In addition we would like to investigate our hypothesis that RhoH is a general modulator of the cellular activity of TLR expressing cells. The project will therefore be performed in close collaboration with the groups of Prof. Heeg (dendritic cells), Prof. Dalpke (macrophages), Prof. Watzl (NK-cells) and Dr. Bekeredjian-Ding (B-cells).

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Dr. Katharina Kubatzky
Dept. of Medical Microbiology and Hygiene
Im Neuenheimer Feld 324
69120 Heidelberg, Germany
e-mail: katharina.kubatzky(at)med.uni-heidelberg.de