Sickle cell disease (SCD) is a devastating hemolytic disease characterized by recurring episodes of painful vaso-occlusion, leading to ischemia-reperfusion injury and organ damage. Despite significant advances in the knowledge of sickle hemoglobin and red blood cells, we still lack a clear understanding of the pathophysiology and treatment of vaso-occlusion. It is now understood that oxidative stress is a trigger for vascular inflammation which promotes vaso-occlusion. Recently the critical roles of endothelial cell activation and inflammation in vaso-occlusion have been recognized, in part due to the development of transgenic murine models of SCD. However, a critical gap exists in explaining how does the sickle patient defend or adapt to excessive hemolysis with the release of hemoglobin/heme/iron into the vasculature and the exuberant production of reactive oxygen species. To remove this heme burden and lessen the oxidative stress, the vasculature increases the expression of heme oxygenase-1 (HO-1). HO-1 is a highly adaptable anti-inflammatory defense against excessive heme burdens. We hypothesize that HO-1, an adaptive, anti- inflammatory gene, plays a critical role in the inhibition and resolution of vaso-occlusion in SCD.
In Specific Aim 1, we will test whether HO-1 and its downstream products, including carbon monoxide, biliverdin/bilirubin and ferritin, manipulated pharmacologically or with gene therapy, will prevent hypoxia/reoxygenation-induced stasis, ameliorate organ pathology and prolong life span in transgenic sickle mice.
In Specific Aim 2, we will identify the mechanisms whereby HO-1 modulates SCD in SCD by examining the effects of HO-1 and its products on oxidative stress, NF-kB activation and endothelial cell adhesion molecule expression. We will demonstrate that adaptative increases in HO-1 activity in SCD are inadequate to handle the excessive heme burden. We expect that further upregulation of HO-1 activity and/or its downstream products will be important strategies to develop innovative new therapies to prevent and treat vaso-occlusion in SCD. This research on inflammation using mouse models of sickle cell anemia wilt identify new targets for drug therapies to alleviate the complications of SCD. These new treatments should decrease sickle crises, prevent organ damage, improve quality and length of lives of sickle cell anemia patients. ? ? ?
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