Sickle cell disease (SCO) is a devastating hemolytic disease characterized by recurring episodes of painfulvaso-occlusion, leading to ischemia-reperfusion injury and organ damage. Despite significant advances inthe knowledge of sickle hemoglobin and red blood cells, we still lack a clear understanding of thepathophysiology and treatment of vaso-occlusion. It is now understood that oxidative stress is a trigger forvascular inflammation which promotes vaso-occlusion. Recently the critical roles of endothelial cell activationand inflammation in vaso-occlusion have been recognized, in part due to the development of transgenicmurine models of SCO. However, a critical gap exists in explaining how does the sickle patient defend oradapt to excessive hemolysis with the release of hemoglobin/heme/iron into the vasculature and theexuberant production of reactive oxygen species. To remove this heme burden and lessen the oxidativestress, the vasculature increases the expression of heme oxygenase-1 (HO-1). HO-1 is a highly adaptableanti-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 SCO.
In SpecificAim 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 preventhypoxia/reoxygenation-induced stasis, ameliorate organ pathology and prolong life span in transgenic sicklemice.
In Specific Aim 2, we will identify the mechanisms whereby HO-1 modulates vasooclusion intransgenic sickle mice by examining the effects of HO-1 and its products on oxidative stress, NF-kBactivation and endothelial cell adhesion molecule expression. We will demonstrate that adaptative increasesin HO-1 activity in transgencic sickle mice are inadequate to handle the excessive heme burden. We believethat further upregulation of HO-1 activity and/or its downstream products will be important strategies todevelop innovative new therapies to prevent and treat vaso-occlusion in SCO. This research on oxidativestress and inflammation using mouse models of SCO will identify new targets and drug therapies to alleviatethe complications of SCO. We expect these new treatments will decrease sickle crises, prevent organdamage, improve quality and length of lives of sickle cell anemia patients.
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