Julie A. Oliver Assistant Professor B.S. Univ. WI-Eau Claire, 1982 Ph.D. Univ. WI-Madison, 1992 Postdoctoral Fellowships Blood Research Institute, Milwaukee, WI, 1992-1994 Center for Thrombosis & Hemostasis, Univ. North Carolina, 1994-1999	Office: Lapham N209 Phone: 414-229-4317 FAX: 414-229-3926 Email: joliver@uwm.eduu Electronic Reserve Materials:
Mammalian Cell Biology

Research Interests

My lab integrates study of cell biology, biochemistry, and hematology. The cell model we use most extensively is the human platelet. We are interested in learning about how platelets and other blood cells interact with proteins of the coagulation cascade. In addition, we are interested in how adhesion molecules expressed on the surface of blood cells control interactions of the cells with: (1) the layer of endothelial cells lining blood vessels; (2) the extracellular matrix below the endothelial layer that is exposed to blood upon injury; and (3) other blood cells. Specific projects include: A. Cell-Mediated Coagulation. Coagulation function is tested through in vitro assays that rely on non-physiologic reagents to provide the negatively charged surface upon which the proteolytic reactions of the coagulation cascade occur. We know that activated cells provide the appropriate surface for the coagulation reactions to proceed in vivo. We have developed an in vitro model system using tissue factor (TF)-bearing cultured cells to initiate coagulation. We are able to measure the extent of platelet activation and thrombin (IIa) generation that result from various experimental manipulations. This system produces results more closely resembling the status of patients than traditional clinical assays often do. Using cell-based methods, we are able to address some of the most challenging questions in coagulation research, including investigation of the mechanisms underlying both hemostasis and thrombosis. B. Assembly of Coagulation Complexes on Cell Surfaces. Proteins of the coagulation cascade are produced primarily in the liver and secreted into the blood plasma. However, some synthesis occurs in other cells of the vascular system. For example, factor V (the non-proteolytic cofactor of the proteolytic complex which produces thrombin from prothrombin) is also synthesized in platelet precursors in the bone marrow, and stored in secretory granules of mature, circulating platelets. There is evidence to suggest that platelet-derived factor V differs from plasma factor V in some properties, including its susceptibility to inactivation. We are studying whether platelet-derived factor V is preferentially incorporated into prothrombinase (Va/Xa) complexes on the surface of activated platelets. We make use of proteins and antibodies directly conjugated to colloidal metals that we can detect and distinguish from one another in the electron microscope. We prepare these colloidal nanoparticles in different sizes and shapes by chemical reduction of salts of different electron dense metals. Colloidal gold nanoparticles are commonly used in electron microscopy and can be purchased as commercial reagents. The synthesis of nanoparticles made from other heavy metals and their application to biological systems is an ongoing development of technology. C. Therapeutic Targeting of Activated Platelets. Platelets that have been activated and aggregated are vital to normal hemostasis. However, they are also central in forming the clots that result in heart attack and stroke. The mechanism of action of daily aspirin taken to prevent heart attacks is the inhibition of platelet function. If we were able to specifically eliminate aggregates of activated platelets, it would offer a new therapeutic approach to cardiovascular disease. This is of special significance in stroke, for which very few effective treatment options are currently available. We are studying the targeting of activated platelets with magnetic nanoparticles followed by exposure to an oscillating magnetic field. The nanoparticles are directed selectively to activated platelets via conjugation to proteins or antibodies that bind to activated, but not unactivated, cells. D. Role of Inflammation in Cardiovascular Disease. The pathology underlying the development of atherosclerotic lesions is inflammation. During inflammation, adhesion molecules are expressed on the surface of endothelial cells and blood cells that promote their interaction. Subsequent to the interaction of endothelium and white blood cells, the white blood cells are able to migrate across the endothelium into the extravascular space. Soluble products secreted by the extravascular leukocytes recruit other white blood cells and fibroblasts into the area. This is a desirable process during wound healing, but in the absence of injury, it can result in a plaque. We are interested in learning which molecules control the inappropriate interaction of leukocytes and endothelium, and how that inflammation can be blocked without compromising the ability of the individual to fight infection or heal following injury.

Selected Publications

1. Meyer, DA, R Bleher, IK Kandela, JA Oliver, RM Albrecht. 2006. The development of alternative markers for transmission electron microscopy and correlative transmission electron and light microscopy, Microsc Microanal 12(Suppl 2):32-33. 2. Meyer, DA, JA Oliver, RM Albrecht. 2005. A method for the quadruple labeling of platelet surface epitopes for transmission electron microscopy, Microsc Microanal 11(Suppl 2):142. 3. Uchida, J, Y Hamaguchi, JA Oliver, JV Ravetch, JC Poe, KM Haas, and TF Tedder. 2004. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy, J Exp Med, 199:1659-1669. 4. Haas, KM, FR Toapanta, JA Oliver, JC Poe, JH Weis, DR Karp, JF Bower, TM Ross, and TF Tedder. 2004. Cutting edge: C3d functions as a molecular adjuvant in the absence of CD21/35 expression, J Immunol, 172:5833-5837. 5. Allen, GA, AS Wolberg, JA Oliver, M Hoffman, HR Roberts, and DM Monroe. 2004. Impact of procoagulant concentration on rate, peak, and total thrombin generation in a model system, J Thromb Haemost, 2:402-413. 6. Uchida, J, Y Lee, M Hasegawa, Y Liang, A Bradney, JA Oliver, K Bowen, DA Steeber, KM Haas, JC Poe, and TF Tedder. 2004. Mouse CD20 expression and function, Int Immunol, 16:119-129. 7. Oliver, JA, DM Monroe, FC Church, H. Roberts, and M Hoffman. 2002. Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces, Blood, 100:539-546. 8. Oliver, JA, DM Monroe, HR Roberts, and M Hoffman. 1999. Thrombin activates factor XI on activated platelets in the absence of factor XII, Arterioscler Thromb and Vasc Biol, 19:170-177. 9. Chang, J-Y, DM Monroe, JA Oliver, and HR Roberts. 1999. TFPI , a second product from the mouse tissue factor pathway inhibitor (TFPI) gene, Thromb Haemost, 81:45-49. 10. Thomas, DW, RB Mannon, PJ Mannon, A Latour, JA Oliver, M Hoffman, O Smithies, BH Koller, and TM Coffman. 1998. Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2, J Clin Invest, 102:1994-2001. 11. Monroe, DM, M Hoffman, JA Oliver, and HR Roberts. 1998. A possible mechanism of action of activated factor VII independent of tissue factor, Blood Coag Fibrinol, 9 (suppl 1):S15-S20. 12. Kjalke, M, DM Monroe, M Hoffman, JA Oliver, M Ezban, U Hedner, and HR Roberts. 1998. The effects of activated factor VII in a cell-based model for tissue factor-initiated coagulation, Blood Coag Fibrinol, 9 (suppl 1):S21-S25. 13. Chang, J-Y, DM Monroe, JA Oliver, DK Liles, and HR Roberts. 1998. Cloning, expression, and characterization of mouse tissue factor pathway inhibitor (TFPI), Thromb Haemost, 79:306-309. 14. Roberts, HR, DM Monroe, JA Oliver, J-Y Chang, and M Hoffman. 1998. Newer concepts of blood coagulation, Haemophilia, 4:331-334. 15. Monroe, DM, M Hoffman, JA Oliver, and HR Roberts. 1997. Platelet activity of high-dose factor VIIa is independent of tissue factor, Br J Haematol, 99:542-547. 16. Kjalke, M, JA Oliver, DM Monroe, M Hoffman, M Ezban, U Hedner, and HR Roberts. 1997. The effect of active site-inhibited factor VIIa on tissue factor-initiated coagulation using platelets before and after aspirin administration, Thromb Haemost, 78:1202-1208. 17. Hudetz AG, JA Oliver, JD Wood, PJ Newman, and JP Kampine. 1997. Leukocyte adhesion in pial cerebral venules after PMA stimulation and ischemia/reperfusion in vivo, Adv Exp Med Biol, 411:513-518. 18. Hoffman, M, DM Monroe, JA Oliver, and HR Roberts. 1995. Factor IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation, Blood, 86:1794-1801. 19. Goldberger, A, KA Middleton, JA Oliver, C Paddock, H-C Yan, HM DeLisser, SM Albelda, and PJ Newman. 1994. Biosynthesis and processing of the cell adhesion molecule PECAM-1 includes production of a soluble form, J Biol Chem, 269:17183-17189.