Professor and Chair
Department of Biochemistry & Biophysics
- CIB1 in cancer
- Lipid signaling in platelet function
- Sickle cell disease
Cancer and CIB
Cancerous tumor cells often proliferate rapidly. Some cancer cell types appear to be addicted to CIB1 for survival. We find that when we knockdown CIB1 in breast and neuroblastoma cancer cells, the cells die by an unusual mechanism that involves GAPDH translocation to the nucleus. We also find that this cell death appears to be so potent because loss of CIB1 causes two oncogenic pathways to fail: the PI3K/AKT pathway and the RAS/RAF/MEK/ERK pathway. However, normal cells do not appear to be addicted to CIB1 for survival. Moreover, once tumors grow beyond a few mm in size, they require blood vessels to provide nourishment in order to grow further. Endothelial cells are essential for blood vessel formation. CIB1 is expressed in multiple cell types, including endothelial cells. We found that efficient tumor-induced blood vessel growth depends upon CIB1. If endothelial cells do not express CIB1, the cells grow more slowly and tumor-induced blood vessel formation is impaired. We have also generated a CIB1 knockout mouse and studied the consequences of a lack of CIB1 on tumor growth in vivo. These data suggest that CIB1 may be a promising anti-cancer target.
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, also induce these thrombotic events. Under pathologic conditions, when the blood vessel has formed cholesterol-containing atherosclerotic plaques, these plaques can rupture, causing platelets become activated and aggregate at these sites, potentially completely blocking blood flow. We wish to better understand the biochemical pathways and mechanisms involved in platelet aggregation in order to identify new targets for drug development.
Sickle Cell Disease
Sickle cell patients suffer from painful vaso-occlusive crises, which are believed to be due to the abnormal adhesion of multiple blood cell types to the blood vessel wall. These cell types appear to include the red cells themselves, white cells and platelets. 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 discovered that the sickle cell has the ability to upregulate its state of adhesion in response to physiologic/pathologic agonists such as thrombospondin and epinephrine. This is an important discovery, since signal transduction pathways in sickle cells are not well characterized, but are likely to provide drug targets to control vaso-occlusive crises. We are currently studying the contribution of neutrophil-mediated inflammation to sickle cell disease.