Tomas
Mustelin
MD, PhD
Education & Training:
MD, University of Helsinki Finland (1985-1987)
D. Med. Sci., University of Helsinki, Finland (1988)
Internship in Rheumatology & Lung Diseases, Kiljava Hospital, Finland (1987-1988)
Post Doctoral Training in Research, Scripps Clinic, La Jolla, CA (1988-1990)
Internship in Family Practice, Kirkkonummi-Siuntio Health Station. Finland (1990)
Enterprise Leadership, Harvard Business School, Boston, MA (2013)
Research Interests:
Dr. Mustelin has been a professor since 1999 and has published over 230 papers. During a 10-year sabbatical in the biotech industry, he served as Vice President and directed research and discovery of novel therapeutics; his teams delivered 24 candidate therapeutics into clinical trials, many of which are efficacious in phase 2 and 3 clinical trials in patients with serious immune-mediated diseases and hematopoietic malignancies. His current research is focused on elucidating the molecular underpinnings of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ANCA-associated vasculitis (AAV), primary Sjögren’s syndrome (pSS), and other autoimmune conditions.
Neutrophils are important in the initiation and propagation of RA, in part because they mediate pathogenic citrullination of a multitude of proteins and cell types in the joint. We are exploring the mechanisms by which pathological citrullination occur in RA patients, the impact of citrullination of interesting proteins, and the regulation of the citrullinating enzymes PAD2 and PAD4.
Another interest is the hypothesis that long interspersed nuclear elements (LINE1) drive type I interferon production in SLE and related diseases by triggering specific nucleic acid sensors. We will verify that this pathway operates in SLE and pSS patients and will test if inhibition of the LINE1 reverse transcriptase will stop IFN production and be therapeutically beneficial for patients.
Continuing from the original discovery of the PTPN22 polymorphism by our lab in 2004, we plan to study how PTPN22 variants affect disease-relevant pathways and cell types in RA, SLE, and AAV. Finally, we will be looking for opportunities to discover and develop new therapeutics for RA, SLE, pSS, and AAV, based on novel insights into disease pathogenesis.
My NCBI:
Publications:
Mustelin, T., Coggeshall, K.M., Isakov, N. & Altman, A. (1990). Tyrosine phosphorylation is required for T cell antigen receptor-mediated activation of phospholipase C. Science, 247, 1584-1587.
Virolle, T., Adamson, E.D., Baron, V., Birle, D., Mercola, D., Mustelin, T. & de Belle, I. (2001). PTEN is directly transactivated in vivo by Egr-1 during irradiation-induced signalling. Nature Cell Biology 3, 1124-1128.
Alonso, A., Rahmouni, S., Williams, S., van Stipdonk, M., Jaroszewski, L., Godzik, A., Abraham, R.T., Schoenberger, S. & Mustelin, T. (2003). Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nature Immunology 4, 44-48.
Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A., Hunter, T., Dixon, J.E., and Mustelin, T. (2004). Protein tyrosine phosphatases in the human genome. Cell 117, 699-711.
Huynh, H., Bottini, N., Williams, S., Cherepanov, V., Musumeci, L., Saito, K., Bruckner, S., Vachon, E., Wang, X., Kruger, J., Chow, C.-W., Pellecchia, M., Monosov, E., Greer, P., Trimble, W., Downey, G. P. & Mustelin, T. (2004). Control of vesicle fusion by a tyrosine phosphatase. Nature Cell Biol. 6, 831-839.
Bottini, N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M., MacMurray, J., Meloni, G.F., Lucarelli, P., Pellecchia, M., Eisenbarth, G.S., Comings, D. & Mustelin, T. (2004). A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genetics 36, 337-338.
Vang, T., Congia, M., Macis, M.D., Musumeci, L., Orru, V., Zavattari, P., Nika, K., Tautz, L., Taskén, K., Cucca, F., Mustelin, T. & Bottini, N. (2005). Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genetics 37, 1317-1319.
Rahmouni, S., Tsutji, T., Huynh, H., Alonso, A., Zhu, C., Cerignoli, F., Louis-dit-Sully, C., Jiang, W. & Mustelin, T. (2006). Loss of the VHR dual-specific phosphatase causes cell cycle arrest and cell senescence. Nature Cell Biology 8, 524-531.
Vang, T., Liu, W.H., Delacroix, L., Wu, S., Vasile, S., Dahl, R., Yang, L., Musumeci, L., Francis, D., Landskron, J., Tasken, K., Tremblay, M.L., Lie, B.A., Page, R., Mustelin, T., Rahmouni, S., Rickert, R.C. & Tautz, L. (2012). LYP inhibits T-cell activation when dissociated from CSK. Nature Chemical Biology 8, 437-446.
Kearley, J., Sanden, C., Silver, J., White, N., Mori, M., Pham, T.-H., Ward, C.K., Criner, G.J. Marchetti, N., Mustelin, T., Erjefält, J.S., Kolbeck, R. & Humbles, A.A. (2015). A critical role for the IL-33/ST2 axes in acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD). Immunity 42, 566–579.
Cohen, E.S., Scott, I.C., Majithiya, J., (7 authors), Sims, D.A., Snaith, M., Vousden, K.A., Strain, M.D., Chan, D., Carmen, S., Flavell, L., Xu, J., Popovic, B., Brightling, C.E., Vaughan, T.J., Butler, R., Lowe, D.C., Higazi, D.R., Corkill, D.J., May, R.D., Sleeman, M.A., Mustelin, T. (2015). Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation. Nature Comm., 6:8327 | DOI: 10.1038/ncomms9327
Mahmoud, T.I., Wang, J., Karnell, J.L., Wang, Q., Wang, S., Naiman, B., Gross, P., Brohawn, P.Z., Morehouse, C., Aoyama, J., Wasserfall, C., Carter, L., Atkinson, M.A., Serreze, D.V., Braley-Mullen, H., Mustelin, T., Kolbeck, R, Herbst, R. & Ettinger, C. (2016). Autoimmune manifestations in aged mice arise from early-life immune dysregulation. Science Transl. Med. 8, 361ra137.
Henault, J., Riggs, J.M., Karnell, J.L., Liarsky, V.M., Shirinian, L.A., Casey, K.A., Smith, M.A., Li, J., Izhak, L., Clarke, L., Ettinger, C., Herbst, R., Petri, M., Clark, M.R., Mustelin, T., Kolbeck, R., Sanjuan, M.A. (2016). Novel pathogenic function of IgE in autoimmunity. Nature Immunology, 17, 196-203.
Stanford, S.M., Aleshin, A.E., Zhang, V., Ardecky, R.J., Hedrick, M.P., Zou, J., Ganji, S.R., Bliss, M.R., Yamamoto, F., Bobkov, A.A., Kiselar, J., Liu, Y., Cadwell, G.W., Khare, S., Yu, J., Barquilla, A., Chung, T.D., Mustelin, T., Schenk, S., Bankston, L.A., Liddington, R.C., Pinkerton A.B. & Bottini, N. (2017). Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase. Nature Chemical Biology 13, 624-632.
Shi, J., Darrah, E., Sims, G.P., Mustelin, T., Sampson, K., Konig, M.F., Bingham, C.O. 3rd, Rosen, A. & Andrade, F. (2018). Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deiminase type 4 in rheumatoid arthritis. Ann. Rheum. Dis. 77, 141-148.