Sarah J Netzel-Arnett
Ph.D.
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| Academic Title:
Assistant Professor |
| Primary Appointment:
Physiology |
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sarnett@som.umaryland.edu |
| Location:
800 W. Baltimore Street, Bio Park
235 |
| Phone:
410-706-8164 |
| Fax:
410-706-8121 |
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Personal History
I completed my doctorate in Molecular Biophysics at Florida State University where I developed synthetic peptides and fluorescent assays to study structure-function relationships of matrix metalloproteinases (MMPs) and their substrates. During my postdoctoral training in cell biology at the National Institute of Health, I investigated the role of plasminogen activation system in the activation of MMPs during keratinocyte invasion on collagen matrices. I then worked at the Holland Laboratory of the American Red Cross, where I began my studies on the physiological function of membrane serine proteases. In 2006, I was appointed to the faculty of the University of Maryland, School of Medicine as a Research Associate in the Department of Physiology. In 2006 I received the Independent New Investigator Award from the School of Medicine. I am currently a member of the International Protease Society and the American Heart Association and serve on the seminar committee for the Center of Vascular and Inflammatory Diseases (CVID) at the School of Medicine.
Research Interests
Ovarian cancer is one of the most lethal female malignancies in the USA. Despite significant improvements in chemotherapy over the past decade, the long term survival of women with advanced ovarian cancer is poor, largely because the rates of disease recurrence are high. The underlying causes of ovarian cancers are little understood despite intensive study, and treatment options for patients with advanced disease are still inadequate. Membrane-anchored serine proteases are overexpressed by metastatic ovarian carcinomas and may contribute to cellular processes that drive advanced disease. In this research project, we propose to determine whether functional inhibition of these proteases impairs ovarian tumor growth and progression, and whether such inhibition can be exploited for new targeted drug therapies.
Membrane Proteases in Endothelial Cell Biology
Proteases mediate processing, activation and degradation of a wide range of proteins and therefore play critical roles in virtually all aspects of cell biology. The long-term goal of our research is to decipher the molecular basis of endothelial cell (EC) morphogenesis and differentiation during capillary lumen formation and stabilization, particularly with regards to proteolytic regulation of these processes. Specifically, we are investigating the functional role of membrane-anchored serine proteases on ECs in tissues undergoing active angiogenesis.
Lab Techniques and Equipment
Comprehensive analysis of protease biology ranging from expression and purification of recombinant proteins in insect cell expression systems followed by affinity chromatography to distinguishing between the active and inactive forms of serine proteases in complex biological samples using activity-dependent probes. Protease profiling assays include zymography (substrate gel electophoresis), kinetic parameters using chromogenic or fluorogenic peptide assays, activation of zymogens and proteolytic processing of protein substrates using an alkaline phosphatase reporter in a cell-based assay system. Isolation and characterization of serine proteases from biological sources. Knockout and transgenic mouse models are utilized to determine the role of individual proteases in tumor progression or during vascularization of tumors and extracellular matrix-based implants.
Collaborators:
§ Dr. Toni M. Antalis (Professor of Physiology, Surgery & CVID). Physiological roles of membrane anchored serine proteases and inhibitors in cell biology, cancer and angiogenesis.
§ Dr. Thomas H. Bugge (National Institute of Health). The role of Type II transmembrane serine proteases in epithelial development, repair, and malignancy.
§ Dr. Alessio Fasano (Professor of Pediatrics, Physiology & Medicine). The control of barrier function in the gastrointestinal tract by a key regulatory protein known as zonulin.
§ Dr. Terez Shea-Donohue (Professor of Medicine & Physiology). Immune regulation of gastrointestinal functions during parasite infection.
Publications
1. Fields, G.B., Netzel-Arnett, S.J., Windsor, L.J., Engler, J.A., Birkedal-Hansen, H., and Van Wart, H.E. (1990) The Proteolytic Activities of Human Fibroblast Collagenase: Hydolysis of a Broad range of Substrates at a Single Active Site. Biochemistry, 29:6670-6677.
2. Netzel-Arnett, S., Mallya, S.K., Nagase, H., Birkedal-Hansen, H., and Van Wart, H.E. (1991) Continuously recording Fluorescent Assays Optimized for Five Human Matrix Metalloproteinases. Anal. Biochem., 195:86-92.
3. Netzel-Arnett, S., Fields, G., Birkedal-Hansen, H., and Van Wart, H.E. (1991) Sequence Specificities of Human Fibroblast and Neutrophil Collagenases. J. Biol. Chem., 266:6747-6755.
4. Netzel-Arnett, S., Sang, Q.X., Moore, W.G.I., Navre, M., Birkedal-Hansen, H., and Van Wart, H.E. (1993) Comparative Sequence Specificities of Human 72- and 92-kDa gelatinases (Type IV Collagenases) and PUMP (Matrilysin). Biochemistry, 32:6427-6432.
5. Liu, S., Netzel-Arnett, S., Birkedal-Hansen, H., and Leppla, S.H. (2000) Tumor Cell-Selective Cytotoxicity of Matrix Metalloproteinase-activated Anthrax Toxin. Cancer Res., 60:6061-6067.
6. Shankavaram, U.T., Lai, W-C., Netzel-Arnett, S., Mangan, P.R., Ardans, J.A., Caterina. N., Stetler-Stevenson, W.G., Birkedal-Hansen, H., Wahl, L.M. (2001) Monocyte Membrane Type 1-Matrix Metalloproteinase: Prostaglandin-Dependent regulation and Role in MMP-2 Activation. J. Biol. Chem., 22:19027-19032.
7. Engelholm, L.H., Nielsen, B.S., Netzel-Arnett, S., Solberg, H., Chen, X-D., Garcia, J.M.L., Lopez-Otin, C., Young, M.F., Birkedal-Hansen, H., Danø, K., Lund, L.R., Behrendt, N., and Bugge, T.H. (2001) The Urokinase Plasminogen Activator Receptor-Associated Protein/Endo 180 is Coexpressed with its Interaction Partners uPAR and Matrix Metalloproteinase-13 during Osteogenesis. Lab. Invest., 81:1403-1414.
8. Netzel-Arnett, S., Mitola, D.J., Chrysovergis, K., Holmbeck, K., Bugge, T.H., and Birkedal-Hansen, H. (2002) Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. J. Biol. Chem., 277:45154-45161.
9. Engelholm LH, List K, Netzel-Arnett S, Cukierman E, Mitola DJ, Aaronson H, Kjoller L, Larsen JK, Yamada KM, Strickland DK, Holmbeck K, Dano K, Birkedal-Hansen H, Behrendt N, Bugge TH. (2003) uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion. J Cell Biol., 160(7):1009-15.
10. Netzel-Arnett, S., Hooper, J.D.. Szabo, R., Madison E.L., Quigley, J.P., Bugge, T.H., Antalis, T.M. (2003) Membrane Anchored Serine Proteases: A rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer and Metastasis Reviews, 22:237-258.
11. Antalis, T.M., Boucaut, K.J. and Netzel-Arnett, S. (2003) Testisin" in 2nd Edition of the Handbook of Proteolytic Enzymes (Eds. Barrett, A.J., Rawlings, N.D., Woessner, J.F. Jr.) Elsevier.
12. Hobson, J.P., Netzel-Arnett, S., Szabo, R., Rehault, S.M., Church, F.C., Strickland, D.K., Lawrence, D.A., Antalis, T.M., and Bugge, T.H. (2004) Mouse DESC1 is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease that Forms Serpin Inhibitory Complexes. J. Biol. Chem., 279(45):46981-94.
13. Manton, K.J., Douglas, M.L., Netzel-Arnett, S., Fitzpatrick, D.R., Nicol, D.L., Boyd, A.W., Clements, J.A. and Antalis, T.M. (2005) Hypermethylation of the 5’ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. British Journal of Cancer., 92(4):760-9.
14. Szabo, R., Netzel-Arnett, S., Hobson, J.P., Antalis, T.M. and Bugge, T.H. (2005) Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem. J., 390(1):231-42.
15. Netzel-Arnett, S., Currie, B.M., Szabo, R., Lin, C-Y., Chen, L-M., Chai, K.X., Antalis, T.M., Bugge, T.H., and List, K. (2006) Evidence for a Matriptase-Prostasin Proteolytic Cascade Regulating Terminal epidermal Differentiation. J. Biol. Chem., 281(44):32941-5.
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