The objective of this application is to provide the minority applicant with an additional experience that will result in her becoming an independent and RO1 funded investigator. The long-range goal of the investigator is to establish the pathophysiological mechanism(s) that link sickling formation and endothelium activation in sickle cell disease. The central hypothesis of this application is that the elevated systemic and local concentrations of cytokines are major contributors to the pathogenesis of irreversible sickle cell formation via alterations of erythrocyte volume regulatory pathways. We will test the hypothesis by characterizing the mechanism(s) by which ET-1 induces dehydration in sickle erythrocytes and the contribution of inducible signaling factors to this effect in sickle cell disease. We plan to test our central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: 1) Identify the mechanism(s) by which ET-1 receptors regulate sickle erythrocyte cellular volume. We will test the hypothesis that ET-1 receptor induces red cell dehydration via protein kinase C activation. 2) Identify the mechanism(s) by which ET-1 receptors regulate cellular Mg in sickle erythrocytes. We hypothesize that the relationship between the Na/Mg exchange and ET-1 receptor is disrupted in sickle erythrocytes leading to activation of the K/CI cotransport which leads to further red cell dehydration in vivo. 3) Identify the effects of ET-1 receptor antagonist treatment on hypoxic induced sickle cell formation in vivo. We hypothesize that these antagonists may blunt ET-1-mediated effects in hypoxic mice. We also hypothesize that this inhibition might be mediated by a reduction in endothelium activation. The research proposed in this application is significant because it will provide novel information for the use of ET-1 receptor antagonists to reduce irreversible sickle cells and a more comprehensive knowledge of erythrocyte volume regulatory mechanism(s) that will help to develop novel strategies to reduce sickle cell formation, and decrease the occurrence of vaso-occlusive episodes.
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