Last Updated: 2/28/2007

Research Interests
Platelets:
Heart attacks, strokes and related thrombotic disorders kill more people each year in the US than any other disease. Circulating platelets, which normally aggregate at sites of vascular injury to prevent blood loss, causes these thrombotic events. Under pathologic conditions, when the blood vessel has formed cholesterol-containing atherosclerotic plaques, these plaques can rupture, causing platelets to aggregate at these sites, potentially completely blocking blood flow. The lab is currently mapping signal transduction pathways that lead to the activation of 2 different integrins, aIIbß3 and a2ß1. The lab is studying the structure and function of the integrin cytoplasmic domain binding proteins (e.g. CIB1) as well as small G-proteins (R-Ras and Rap1) to understand how these proteins relay information to these integrins to regulate their activation state.
Current broad project areas include:
1) Structural studies of CIB1
2) Functional studies of CIB1 in platelets, megakaryocytes, cell lines and murine models
3) Roles and downstream signaling pathways of H-Ras, R-Ras and Rap1 in integrin activation in platelets, megakaryocytes and cell lines




Sickle Cell Disease:
Sickle cell patients suffer from painful vaso-occlusive crises, which are believed to be due to sickle red cell adhesion to the blood vessel wall. This adhesion blocks blood flow in capillaries and causes severe pain and organ damage. Our lab is interested in understanding the mechanisms of the vaso-occlusive crisis. We previously demonstrated that sickle cells adhere to the large adhesive proteins thrombospondin (TSP) and laminin, which are found in the blood and blood vessel wall. More recently, we have discovered that the sickle cell has the ability to upregulate its state of adhesion in response to physiologic/pathologic agonists such as TSP and epinephrine. This is an important discovery, since signal transduction pathways in sickle cells are not well characterized, but are likely to provide therapeutic targets to control vaso-occlusive crises.
Current broad project areas include:
1) Delineating signal transduction pathways and mechanisms of TSP-induced activation of sickle cells via the TSP receptor CD47 or IAP
2) Delineating the signal transduction pathways and mechanisms of epinephrine-induced activation of sickle cell adhesion to laminin
3) Studying the role of inflammatory mediators in sickle cell disease
4) Establishing in vivo models for validation of potential therapeutic targets



Cancer:
Cancerous cells are often more migratory and invasive than their normal counterparts. Migration and invasion involve a host of signaling networks that are still being unraveled. Integrin adhesion receptors play a central role in mediating the increased migration and invasion of these cells by allowing cells to crawl along proteins of the extracellular matrix (ECM). Signaling pathways regulating cell migration and invasion are complex. Some of these signaling pathways initiated by various agonists, chemotactic agents, etc, that directly affect integrin function, while integrin engagement with specific ECM proteins generates intracellular signals that directly affect cellular behavior. Our lab is interested in mapping signal transduction pathways in transformed cells that cause integrins to mediate increased cellular migration and invasion. Intracellular signaling molecules of interest include CIB1, described above, as well as members of the Ras superfamily of small G-proteins. These small G-proteins or GTPases act as molecular switches in cells and are crucial for transmitting fundamental biologic information in cells, regulating everything from rates of cell proliferation, to cytoskeletal structure and states of integrin activation. We have found that some of these small G-proteins (R-Ras, TC21, Cdc42 and Rac) cause cells to acquire a migratory and invasive phenotype, but by very different mechanisms. In ongoing studies we are trying to understand the different mechanisms of transformation by mapping the signaling pathways involved.


Broad project areas include:
1) Further defining the role of CIB1 in regulating cell migration
2) Identifying downstream pathways by which small G-proteins regulate cell motility
3) Determining how small G-proteins affect integrin function

Recent Accomplishments and Honors


2006 Appointed Chair of Biochemistry & Biophysics

2002 Appointed Vice-Chair of Pharmacology, UNC-CH
2003 Recipient of “The First Annual Stewart-Niewiarowski Award for Women in Vascular Biology” from Temple University

2003-2007 Member of the Biomedical Research and Research Training (BRT) Committee of NIGMS

2003-2008 Editorial Board member for the journals BLOOD

2003-2006 Reappointed to a 3rd 3-year term on the Editorial Board of Journal of Cell Biology

Training
B.S., Univ. of IL-Urbana,Chemistry/Biology, 1976
Ph.D. Univ. of IL Med. Ctr., Chicago, Pharmacology, 1982
Postdoctoral, UCSF/Gladstone Fdn, 1982-1985; Staff Res Associate, 1985-1988

Publications
Yuan W., Leisner T. M. McFadden A.W., Wang Z., Larson M.K., Clark S., Boudignon-Proudhan C., Parise L.V. CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbBeta3 activation. J Cell Biol, 172(2):169-75, 2006.

Leisner TM, Liu M, Jaffer ZM, Chernoff J, Parise LV. Essential role of CIB1 in regulating PAK1 activation and cell migration. J Cell Biol 170(3):465-76, 2005.

Holly S.P., Larson M.K. and Parise L.V.: The Unique N-terminus of R-Ras is Required for Rac Activation and Precise Regulation of Cell Migration. Mol Biol Cell. 16(5):2458-69, 2005.

Gentry HR, Singer AU, Betts L, Yang C, Ferrara JD, Sondek J, Parise LV. Structural and biochemical characterization of CIB1 delineates a new family of EF-hand containing proteins. J Biol Chem. 280(9):8407-15, 2005.

Murphy M.M., Zayed M.A., Evans A., Parker C.E., Ataga K.I., Telen M.J., Parise L.V. Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Blood. 105(8):3322-9, 2005.

Parise, L.V., Smyth, S.S., Coller, B.S. “Platelet morphology, biochemistry, and function” Williams Hematology, 7th ed., 2005.

Brittain J.E., Han J., Ataga K.I., Orringer E.P., Parise L.V.: Mechanism of CD47-induced Alpha 4 Beta 1 Integrin Activation and Adhesion in Sickle Reticulocytes. J. Biol. Chem. 279(41):42393-402, 2004.

Zennadi R., Hines P.C., De Castro L.M., Carton J-P, Parise L.V., Telen M.J.: Epinephrine Acts via Erythroid Signaling Pathways to Activate Sickle Cell Adhesion to Endothelium via LW-alphavbeta3 Interactions. Blood, 104(12):3774-81, 2004.

Parise, L.V.: JAM-1 Regulation of Endothelial Cell Migration: Implications for Angiogenesis. Arterioscler. Thromb. Vasc. Biol., 23(12):2119-20, 2003.

Larson M.K., Parise L.V.: Platelets Made to Order. Blood, 102:3859, Capsule Commentary, 2003.

Parise L.V., Telen M.J.: Erythrocyte Adhesion in Sickle Cell Disease. Current Hematology Reports, 2(2):102-108, 2003.

Wang Z., Leisner T.M., Parise L.V.: Platelet alpha2 Beta1 Integrin Activation: Contribution of Ligand Internalization and the alpha2-Cytoplasmic Domain. Blood, 102(4):1307-1315, 2003.

Hines C.P., Zen Q., Burney S.N., Shea D., Ataga K.I., Orringer E.P., Telen M.J., Parise L.V.: Novel Epinephrine and Cyclic AMP-Mediated Activation of BCAM/Lu Dependant Sickle (SS) RBC Adhesion. Blood, 101(8):3281-3287, 2003.

Larson M.K., Chen H., Kahn M.L., Taylor A.M., Fabre J., Mortensen R.M., Conley P.B., Parise L.V.: Identification of P2Y12-dependant and -independant mechanisms of glycoprotein VI-mediated Rap1 activation in platelets. Blood, 101(4):1409-1415, 2003.

Barry W.T., Boudignon-Proudhon C., Shock D.D., McFadden A., Weiss J.M., Sondek J., Parise L.V.: Molecular Basis of CIB Binding to the Integrin AlphaIIb Cytoplasmic Domain. J. Biol. Chem., 277(32):28877-28883, 2002.

A. Bertoni, S. Tadokoro, K. Eto, N. Pampori, L.V. Parise, G.C. White, S.J. Shattil: Relationships between Rap1b, affinity modulation of integrin alphaIIbß3 and the actin cytoskeleton . J. Biol. Chem., 277(28):25715-25721, 2002.

James J. Fiordalisi, Stephen P. Holly, Ronald L. Johnson II, Leslie V. Parise, and Adrienne D. Cox: A distinct class of dominant negative Ras mutants: Cytosolic, GTP-bound Ras effector domain mutants that inhibit Ras signaling and transformation, and enhance cell adhesion. J.Biol. Chem., 277(13):10813-10823, 2002.

Parise, L.V.: "Platelet Activation: Communication with Integrin Cytoplasmic Domains" in Interactions of Blood and the Pulmonary Circulation . Eds, Weir EK, Reeve, Futura Press, NY., 2001.

Brittain, J.E., Mlinar, K.J., Anderson, C. S. Orringer, E.P., Parise, L.V.: Activation of Sickle Red Blood Cell Adhesion via Integrin-Associated Protein (IAP/CD47)-Induced Signal Transduction. J. Clin. Invest., 107(12):1555-62, 2001.

Fabre JE, Nguyen M, Athirakul K, Coggins K, McNeish JD, Austin S, Parise LV, FitzGerald GA, Coffman TM, Koller BH: Activation of the murine EP3 receptor for PGE(2) inhibits cAMP production and promotes platelet aggregation. J Clin Invest, 107(5):603-610, 2001.

Brittain, J.E., Mlinar K.J., C.S. Anderson, Orringer, E.P., Parise, L.V.: Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin. Blood, 977:2159-2164, 2001.

Parise, L.V., Smyth, S.S., Coller, B.S. “Platelet morphology, biochemistry, and function” Williams Hematology, 6th ed., 2001.

E-mail: parise@med.unc.edu
Telephone: (919) 966-2238
FAX: (919) 966-2852
Address: 405 Mary Ellen Jones Bldg., CB# 7260 Chapel Hill, NC 27599
URL: www.med.unc.edu/biochem/ParisePage/center.htm

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