University of Virginia Health System

Email Address: alg4p@virginia.edu

The first involves understanding biochemical mechanisms that link platelet activation by agents like ADP, thrombin, chemokines and collagen, to the participation of these cells in clot formation and wound healing. The fundamental biochemical and structural events in platelet function involve specific interactions of these compounds with receptors on the plasma membrane, which then trigger major responses inside the cell. Dramatic alterations in cell morphology are associated with these biochemical changes; long pseudopodia are extended, intracellular granules are secreted and platelets stick to each other (aggregation) or to molecules such as collagen at the site of a wound (adhesion).

The second area relates to the roles of blood platetets in disease. Two themes are being studied: the first involves how blood lipids such as oxidized low-density lipoprotein (ox-LDL), are involved in causing heart attacks or strokes. The second area targets how specific toxins such as endotoxin (lipopolysaccharide, or LPS) or shiga toxin (STXs, associated with the 'hamburger disease') may stimulate blood clotting and cardiovascular problems.

Specific research questions are as follows:

1) How is platelet function controlled by alterations in the synthesis and degradation of cyclic AMP and cyclic GMP, including the involvement of new drugs such VIOXX and CELEBREX and nitric oxide?
2) The roles of chemokines produced during inflammation and activation of platelet function is being actively studied. How do LPS and Shiga toxins cause strong inflammation and how does this leads to platelet activation and interaction with white blood cells such as monocytes as well as with endothelial cells.
3) How does Ox-LDL activate platelet function ? Which cell receptors and signal transduction pathways are involved ? and how can these be regulated ?
4) What are the biochemical mechanisms by which LPS stimulates platelet respiration and enhances platelet function. What are the roles of mitochondria in these processes ?