The goal of the Program Project is to advance the investigators' understanding of the vascular pathology of sickle cell disease, in the belief that this will hasten development of efficacious therapies for this disease. This program focuses upon several aspects of sickle vascular pathobiology that are important and yet have been relatively neglected in the history of sickle disease investigation. The investigators' strategy is to employ a multidisciplinary group of investigators utilizing a wide variety of approaches including physiology, biochemistry, and cell and molecular biology. Project 1. Endothelial Biology, addresses three examples of probable endothelial perturbation in sickle disease: the ability of thrombospondin to antagonize thrombin receptor signaling in microvascular endothelial cells, the ability of adherent RBC to activate endothelium, and the effect of heme/iron on endothelial status. Project 2. Hemostasis, examines several interrelated aspects of hemostasis including the reasons for excess thrombin generation and abnormal expression of tissue factor activity, the reason for acquired protein S deficiency, and the possibility that sickle red blood cells have a net anticoagulant effect rather than net pro-coagulant effect on sickle blood. Project 3. Renal Injury, examines individual components of an integrative hypothesis that explains the pathogenesis of renal disease including mechanisms underlying early alterations of glomerular hemodynamics, the role of oxidative stress and heme and prostaglandins, as well as the effects of sickle hemoglobin on mesangial and renal tubular epithelial cells. Project 4. Reperfusion Injury, examines the novel idea that sickle disease is an example of ischemia/reperfusion injury physiology. This hypothesis will be specifically tested, and the use of a membrane-permanent iron chelator as a therapeutic approach will be examined. Additionally, the in vivo flow behavior of white blood cells in relationship to this will be examined, as will th impact of WBC/endothelial interaction on RBC microvascular flow. Project 5. Globin Gene, examines the mechanism and impact of butyrate and short chain fatty acids in regulating globin and non-globin gene expression in murine and human systems. Several important sub-themes also are woven among these projects: WBC and RBC adhesion, thrombin, endothelial activation and hypoxia/iron/oxidation in sickle disease. These projects utilize various methodologies, relying extensively on both cell culture and transgenic sickle mice as model systems. Several projects will examine novel therapies in the murine sickle disease model. This highly interactive group of investigations will address multiple pathogenic factor that heretofore have not been identified or considered in the pathophysiology of sickle disease.
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