I was awarded my PhD in Medicine (Biochemistry and Molecular Biology) at Monash University, Victoria, Australia in 2004, where I continued my thesis research as a post-doctoral fellow in the laboratory of Prof. Phillip Bird until 2006. I was then awarded a competitive CJ Martin Overseas Training Fellowship, from the National Health & Medical Research Council (Australia), to continue my post-doctoral training in the laboratory of Prof. Toni Antalis here at the University of Maryland. I became a faculty member of the Department of Physiology in 2012. My research career has focused on understanding the physiological functions of a specialised group of enzymes known as proteases, that mediate the specific cleavage or degradation of other proteins, resulting in a variety of fundamental biological responses.
My thesis studies focused on the biology of the serine protease Granzyme B, a cytotoxic protease used by cells of the immune system to kill virally infected or malignant cells, and also the role of a specific Granzyme B inhibitor (PI-9) in the protection of normal cells during local immune responses, and in the prevention of Granzyme B-mediated auto-immune pathologies in the placenta and testis. Since joining the University of Maryland, the major focus of my research has been to elucidate the role of another serine protease (Matriptase), a multi-domain more complex protease which is found anchored to the cell surface of epithelial tissues such as the skin and intestinal epithelium. After our initial discovery that Matriptase plays a critical role in maintaining the integrity of intestinal epithelium, my research is currently focused on understanding the contribution of Matriptase-mediated barrier formation in the protection from the development of Inflammatory Bowel Diseases such as Crohn's Disease and Ulcerative Colitis, and the mechanisms by which Matriptase expression and activity is regulated.
Matriptase is one of a unique group of serine proteases that is directly tethered to the surface of epithelial cells that line the intestinal tract. We have determined that Matriptase, which is localized to adherens junctions in polarized intestinal epithelial cells, is required for closure of the paracellular pathway through an atypical PKC-mediated signaling pathway that regulates tight junction formation. Recently my research has involved understanding the contribution of Matriptase-mediated barrier formation in Inflammatory Bowel Diseases (IBD). We found that Matriptase expression is markedly down-regulated in human IBD, where increased intestinal permeability is thought to be causally linked to disease pathogenesis. Furthermore, using a murine hypomorph model of Matriptase deficiency we showed that that loss of Matriptase leads to increased disease susceptibility and failure to recover from a murine model of experimental colitis. I have recently discovered that Matriptase requires proteolytic activation by another upstream membrane-anchored protease, called Prostasin, before it can induce intestinal barrier formation, suggesting the existence of a novel proteolytic pathway in this tissue. My current research focuses on the mechanisms by which Matriptase function is regulated, and in the identification of the downstream molecules which are regulated by Matriptase to induce intestinal barrier function.
Buzza, M.S., Martin E.W., Driesbaugh K.H., Desilets A., Leduc R., and Antalis T.M. (2013) Prostasin is required for matriptase activation in intestinal epithelial cells to regulate closure of the paracellular pathway. J Biol Chem. Feb 26. [Epub ahead of print]
Netzel-Arnett S, Buzza M. S., Shea-Donohue T, Desilets A, Leduc R, Fasano A, Bugge H, Antalis, TM. (2012) Matriptase protects against experimental colitis and promotes intestinal barrier recovery. Inflammatory Bowel Diseases. 18(7):1303-14.
Antalis, TA., Buzza M. S., Hodge, KM, Hooper, JD. and Netzel-Arnett, S. (2010). The Cutting Edge: Membrane Anchored Serine Protease Activities in the Pericellular Microenvironment. Invited Review. Biochem J. Jun 15;428(3):325-46
Buzza, M.S., Netzel-Arnett, S., Shea-Donohue, T., Zhao, A., Lin, C-Y., List, K., Szabo, R., Fasano, A., Bugge, T.H. and Antalis, T.A. (2010). The membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine. Proc Natl Acad Sci U S A. Mar 2;107(9):4200-5 *a commentary on this manuscript was published in the "Highlights from the Literature" section of the journal Physiology, 25:128-131, 2010.
Tripathi, A., Lammers, K. M., Goldbulm, S., Shea-Donohue, T., Netzel-Arnett, S., Buzza, M.S., Antalis, T.M., Vogel, S.N, Zhao, A., Yang, S., Arrietta, M.C., Meddings, J.B. and Fasano, A. (2009). Identification of human Zonulin, a physiological modulator of tight junctions, as Pre-haptoglobin-2. Proc Natl Acad Sci U S A. 106(39):16799-804.
Tonnetti, L., Netzel-Arnett, S., Darnell, G.A., Hayes, T., Buzza, M.S., Anglin, I.E., Suhrbier, A. and Antalis, T.M. (2008). SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival. Cancer Res. 68(14):5648-57.
Buzza, M.S., Dyson, J.M., Choi, H., Gardiner E.E., Andrews, R.K., Kaiserman, D., Mitchell, C.A., Berndt, M.C., Dong, J.F. and Bird, P.I. (2008). Antihemostatic activityof human granzyme B mediated by cleavage of von Willebrand factor. J Biol Chem. 283(33):22498-504.
Buzza, M.S. and Bird P.I. (2006). Extracellular granzymes: current perspectives. Biol. Chem. 387(7):827-37.
Buzza, M.S., Hosking P. and Bird, P.I. (2006). The granzyme B inhibitor, PI-9, is differentially expressed during placental development and up-regulated in hydatidiform moles. Placenta. 27(1):62-9.
Buzza, M.S., Zamurs, L., Sun, J., Bird, C.H., Smith, A I., Trapani, J.A., Froelich, C.J., Nice, E.C. and Bird P.I. (2005). Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin and laminin. J Biol Chem. 280(25):23549-58.
Law R. H., Irving, J.A., Buckle, A.M., Ruzyla K., Buzza, M., Bushtannyk-Puhalovich T.A., Beddoe, T. C., Nguyen K., Worrall, D.M., Bottomley, S.P, Bird, P.I., Rossjohn J., Whisstock, J.C. (2005). The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix. J Biol Chem. 280(23): 22356-64.
Hirst C.E., Buzza, M.S., Bird, C.H., Warren, H.S., Cameron, P.U., Zhang, M., Ashton-Rickardt, P.G. and Bird, P.I. (2003). The intracellular granzyme B inhibitor PI-9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency. J Immunol. 170(2): 805-15
*Buzza, M.S., *Hirst, C.E., Sutton, V.R., Trapani, J.A., Loveland, K.L. and Bird, P.I. (2001). Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction. Mol Hum Reprod. 7(12): 1133-42. *Equal first author with Hirst, as noted on title page.
Bird, C.H., Blink, E.J., Hirst, C.E., Buzza, M.S., Steele, P.M., Sun, J., Jans, D.A. and Bird P.I. (2001). Nucleocytoplasmic distribution of the ovalbumin serpin PI-9 requires a non-conventional nuclear import pathway and the export factor Crm1. Mol Cell Biol. 21(16): 5396-407.
Buzza, M.S., Hirst, C.E., Bird, C.H., Hosking, P., McKendrick, J. and Bird P.I. (2001). The granzyme B inhibitor, PI-9, is present in endothelial cells and mesothelial cells, suggesting it protects bystander cells during immune responses. Cell Immunol. 210(1): 21-9.
Sun, J., Bird, C.H., Buzza, M.S., McKee, K.E., Whisstock, J.C. and Bird, P.I. (1999). Expression and purification of recombinant human granzyme B from Pichia pastoris. Biochem Biophys Res Commun. 216(2):251-5.