Two key questions underly the problem of microcirculatory thrombosis: What triggers its occurrence in small blood vessels and at what point does it become irreversible, leading to organ damage and tissue necrosis. Since the most frequent underlying condition for microcirculatory thrombosis is endotoxin-producing gram-negative bacteremia, a cause of an estimated 18,000 deaths per year in the US, we plan to continue our studies in two ways. One is based on a search for endotoxin binding sites (receptors) on the cells involved in microcirculatory thrombosis. The second way is based on regulating cellular function to prevent endotoxin- induced changes, including Lipid A-mediated activation of protein kinase C in human platelets and other cells. The role of interleukin I in mediating Lipid A-induced vascular changes will be evaluated. To this end the development and application of inhibitors modifying cellular responses to endotoxin offers a novel approach to endotoxic shock and microvascular thrombosis. Another major goal of our studies is further characterization of clumping factor on staphylococci, the most primitive organisms known to have a fibrinogen receptor. We plan to locate the binding domain for human fibrinogen gamma chain carboxy terminal receptor recognition site and establish the molecular mechanism of formation of fibrinogen-staphylococcal clumping linkages. We plan to develop a functional model of the clumping receptor-fibrinogen interaction as a prototype for a similar type of interaction of human fibrinogen with eukaryotic receptors. Thus, our research should expand the knowledge of (1) microcirculatory thrombosis triggered by endotoxin, in particular the interaction of Lipid A with the membrane of human platelets and human endothelial cells; (2) the molecular mechanism whch determines when microvascular thrombosis is reversible and when it becomes irreversible, as related to refractoriness of vascular cells to physiological regulatory mechanisms. The practical results of these fundamental approaches will be the development of a new class of inhibitors that would be useful for blocking the effects of endotoxin and staphylococci in microcirculatory thrombosis.
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