Leslie Parise, PhD

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.

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.

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

RECENT PUBLICATIONS:

Brittain JE, Knoll CM, Ataga KI, Orringer EP, Parise LV. Fibronectin bridges monocytes and reticulocytes via integrin alpha4beta1. Br J Haematol. 2008 Jun;141(6):872-81.

Brittain JE, Parise LV. The alpha4beta1 integrin in sickle cell disease. Transfus Clin Biol. 2008 Feb-Mar;15(1-2):19-22.

Ataga KI, Moore CG, Hillery CA, Jones S, Whinna HC, Strayhorn D, Sohier C, Hinderliter A, Parise LV, Orringer EP. Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. Haematologica. 2008 Jan;93(1):20-6.

Zayed MA, Yuan W, Leisner TM, Chalothorn D, McFadden AW, Schaller MD, Hartnett ME, Faber JE, Parise LV. CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis. Circ Res. 2007 Nov 26;101(11):1185-93.

Liu J, DeNofrio J, Yuan W, Wang Z, McFadden AW, Parise LV. Genetic manipulation of megakaryocytes to study platelet function. Curr Top Dev Biol. 2008;80:311-35. Review.

Brittain JE, Parise LV. Cytokines and plasma factors in sickle cell disease. Curr Opin Hematol. 2007 Sep;14(5):438-43. Review.

Lee SP, Ataga KI, Zayed M, Manganello JM, Orringer EP, Phillips DR, Parise LV. Phase I study of eptifibatide in patients with sickle cell anaemia. Br J Haematol. 2007 Nov;139(4):612-20.

Leisner TM, Yuan W, DeNofrio JC, Liu J, Parise LV. Tickling the tails: cytoplasmic domain proteins that regulate integrin alphaIIbbeta3 activation. Curr Opin Hematol. 2007 May;14(3):255-61.

Yuan W, Leisner TM, McFadden AW, Clark S, Hiller S, Maeda N, O'Brien DA, Parise LV. CIB1 is essential for mouse spermatogenesis. Mol Cell Biol. 2006 Nov;26(22):8507-14.

Lee SP, Ataga KI, Orringer EP, Phillips DR, Parise LV. Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1626-31.

Yuan W, Leisner TM, McFadden AW, Wang Z, Larson MK, Clark S, Boudignon-Proudhon C, Lam SC, Parise LV. CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation. J Cell Biol. 2006 Jan 16;172(2):169-75.