Dr. William S. Hendey

The regulation of neutrophil motility by integrin receptors and the effects of apoptosis on neutrophil attachment and motility.

Post Doctoral Research:
Post doctoral Advisor: Frederick R. Maxfield Ph.D.
Post doctoral research examined the role of Ca2+ in the regulation of neutrophil motility. Earlier work in the lab indicated that motile neutrophils show transient increase in cytoplasmic Ca2+ that correlate with motility. We determined thatCa2+regulates neutrophil motility in a substrate dependent fashion. For example, motility on fibronectin and vitronectin is calcium dependent. However motility on albumin is not affected by buffering calcium. We also determined that motility on vitronectin requires the activation of the calcium dependent phosphatase calcineurin. Thus motility on fibronectin and vitronectin are both calcium dependent but proceed through different mechanisms with calcineurin playing a role in the vitronectin pathway and not in the fibronectin pathway.

Doctoral Dissertation:
'Mitogenic Signal Transduction in WS-1 Human Fibroblasts: Thrombin Effects on Phosphoinositide Metabolism, Intracellular Calcium and pH.'
Ph.D. Dissertation Advisor: Mark Mamrack Ph.D.
Characterized mitogenic stimuli for a human fibroblast cell. We determined that thrombin was mitogenic, but many other growth factors were not mitogenic for these cells. We measured the effect of thrombin stimulation on phosphoinositide turnover, Ca2+ and pHi. We determined that changes in Ca2+were necessary for the thrombin induced increases in pHi and DNA synthesis. During this work it was determined that the increases in pHi were due to the activationof the Na+/H+ exchanger. In addition, we determined that either increases in intracellular Ca2+ or activation of Protein Kinase C could activate the Na+/H+ exchanger independently of the other.These findings came from a physiological analysis of the Na+/H+ exchanger activation in response to thrombin, Calcium ionophores, PMA and Protein Kinase C inhibitors. We concluded that thrombin activates the Na+/H+ exchanger through its effect on intracellular calcium independent of PKC.
This work was completed in 1989. Since this time other labs have isolated theNa+/H+ exchanger and have determined that there are two independent sites on the cytoplasmic tail of the exchanger that regulate its activity. One site binds calmodulin and regulates the Ca2+ activation response. Another site mediates activation through phosphorylation.

Continuing research investigates how the onset of apoptosis down regulates PMN function. This loss of function occurs before the PMN can be recognized as apoptotic and be removed by phagocytic cells.
We are investigating how can apoptotic signaling pathway involving ceramide and PKC delta can change beta 2 integrin mediated adhesion.

We have identified an apoptotic pathway that controls PMN adhesion to endothelial cells.
This pathway offers potential new targets that control the recruitment of PMN to sites of inflammation.