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