Ruprecht-Karls-Universität Heidelberg
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Kubatzky0119 - Scientist (f/m) / PhD position
Project no:
Kubatzky0119

Project leader:

Project supervisor:
Hieke-Kubatzky, Katharina
Application deadline:
5. Oct 2019
Start of PhD project:
1. Dec 2019

Project description:

Title:
The (immune)metabolism of the developing osteoclast
Summary:
Osteoclasts are haematopoietic cells that develop under the influence of the cytokines M-CSF and RANKL from the monocyte/macrophage lineage and resorb bone (Teitelbaum, 2000). Under inflammatory conditions, macrophage activity and osteoclast differentiation mutually influence each other, for example through the release of pro-inflammatory cytokines that also act as osteoclastogenic factors (Alves et al., 2016). Recently, the influence of metabolism on macrophage function and plasticity came into focus, however, the impact of metabolism on osteoclast differentiation is less well studied. As bone resorption is an energy demanding process, metabolic activity is a central point in osteoclast differentiation and often found to be deregulated in diseases with increased osteoclast formation (Kubatzky et al., 2018). Due to the close relationship between inflammation and osteoclast differentiation, a better understanding of the metabolic aspects of the macrophage/osteoclast plasticity is warranted. Our previous research used the osteoclastogenic protein toxin Pasteurella multocida toxin (PMT) to trigger osteoclastogenesis (Kubatzky, 2012;Chakraborty et al., 2017). Our recent data showed that PMT manipulates the differentiating osteoclasts into a hypermetabolic state and that the metabolic activity is an essential factor in the ability of osteoclasts to perform processes such as fusion or resorption (Kloos et al., 2015). We identified the heterotrimeric protein Gαq as well as its downstream effectors STAT3 and Pim-1 to be key signalling molecules in PMT-mediated osteoclastogenesis (Kubatzky et al., 2013;Chakraborty et al., 2017). Interestingly, these proteins are also associated with diseases such as multiple myeloma or arthritis where they take part in the formation of hypermetabolic macrophages that have increased glycolytic activity that results in increased bone resorption. Cell metabolism is already a well-established target in cancer therapy, but has only recently be discovered as an equally interesting target in inflammatory diseases.
References:
Alves, C.H., Farrell, E., Vis, M., Colin, E.M., and Lubberts, E. (2016). Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside-a Comprehensive Review. Clin Rev Allergy Immunol 51, 27-47.

Chakraborty, S., Kloos, B., Harre, U., Schett, G., and Kubatzky, K.F. (2017). Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis. Front Immunol 8, 185.

Kloos, B., Chakraborty, S., Lindner, S.G., Noack, K., Harre, U., Schett, G., Kramer, O.H., and Kubatzky, K.F. (2015). Pasteurella multocida toxin- induced osteoclastogenesis requires mTOR activation. Cell Commun Signal 13, 40.

Kubatzky, K.F. (2012). Pasteurella Multocida and Immune Cells. Curr Top Microbiol Immunol.

Kubatzky, K.F., Kloos, B., and Hildebrand, D. (2013). Signaling cascades of Pasteurella multocida toxin in immune evasion. Toxins (Basel) 5, 1664-1681.

Kubatzky, K.F., Uhle, F., and Eigenbrod, T. (2018). From macrophage to osteoclast - How metabolism determines function and activity. Cytokine 112, 102-115.

Teitelbaum, S.L. (2000). Bone resorption by osteoclasts. Science 289, 1504-1508.

Methods that will be used:
mammalian tissue culture (cell lines and bone marrow derived macrophages), FACS, Western Blot, RT-PCR, cell fractionation, µCT measurement to determine bone parameters, bone resorption assays, metabolic assays
Cooperation partners:
We collaborate with Dr. Florian Uhle (Anaesthesiologie) and Dr. Margarida Souto-Carneiro (Rheumatologie).
Personal qualifications:
The applicant should have a a degree in Biology, Biochemistry or equivalent. We are looking for a highly motivated researcher to conduct challenging research at the interface of biochemistry and immunology. Experience in biochemistry, molecular biology and animal handling is preferred.
Keywords:
Osteoclast differentiation, immune metabolism, inflammation, macrophage plasticity