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(WIS) Inhibition of osteoclastogenesis for the prevention of bone wasting in human disease


Project Description

Osteoclasts (OCLs) are phagocytic cells that degrade bone as part of its homeostatic regulation. Abnormal activity of OCLs in several pathologies, such as osteoporosis and cancer, results in loss of bone mass, increased risk of fractures, and in an overall increase in significant morbidity and mortality. Thus, there is interest in the development of therapeutics for pharmacological inhibition of osteoclastogenesis as a strategy to counteract excessive bone degradation. In this project we will use a two-pronged approach for the inhibition of OCL production. We will investigate the mechanism of modulation of the interaction between collagen and the collagen-activated osteoclast-associated receptor OSCAR using customized collagen-based matrices as substrates for OCL culture. We will also investigate the role of the receptor phosphatase PTPRJ in osteoclast differentiation and maturation with the aim of developing small molecule inhibitors of PTPRJ function. Finally, we will investigate possible synergy effects between the modulation of collagen-OSCAR interactions and the inhibition of PTPRJ with small molecule inhibitors. Our study will provide novel approaches for inhibiting bone resorption that can be developed into novel drugs to combat osteoporosis and cancer-related bone loss.

Entry Requirements
Applicants must be from the UK/EU and have obtained (or be about to obtain) a minimum 2:1 Bachelors honours degree or equivalent in a relevant subject area.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Weizmann Institute of Science, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] Bella, J. (2011) Collagen (PCT/GB2011/052217), WO2012063088 A2.
[2] Finkelshtein, E., Lotinun, S., Levy-Apter, E., Arman, E., den Hertog, J., Baron, R. and Elson, A. (2014). Protein tyrosine phosphatases Epsilon and Alpha perform non-redundant roles in osteoclasts. Mol. Biol. Cell 25 (11), 1808-1818.
[3] Levy-Apter, E., Finkelshtein, E., Vemulapalli, V., Li, S.S.-C., Bedford, M.T. and Elson, A. (2014). Grb2 promotes Src activation and podosomal organization by protein tyrosine phosphatase Epsilon in osteoclasts. J. Biol. Chem. 289 (52), 36048-36058.
[4] Granot-Attas, S., Luxenburg, C., Finkelshtein, E. and Elson, A. (2009). PTP Epsilon regulates integrin-mediated podosome stability in osteoclasts by activating Src. Mol. Biol. Cell 20 (20), 4324-4334.
[5] Barnea, M., M. Stein, S. Winograd, M. Shalev, E. Arman, E. Brenner, F. Thalji, M. Kanaan, H. Elinav, P. Stepensky, B. Geiger, J. Tuckermann, and A. Elson. (2018). Massive osteopetrosis caused by giant, non-functional osteoclasts in R51Q SNX10 mice. bioRxiv 332551
[6] An, B., Brodsky, B (2016). Collagen binding to OSCAR: the odd couple. Blood, 127 (5), 521-522.

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