This study will generate a humanized RPE-specific globin gene knockout mouse to elucidate the function of hemoglobin in retinal pigment epithelial (RPE) cells. RPE cells serve many functions essential to the maintenance of outer retinal health and overall visual function. Newly discovered among these, is the production of hemoglobin, a phenomenon once thought to be reserved exclusively for cells of erythroid lineage. We hypothesize that RPE-hemoglobin is important for the maintenance of RPE and retinal morphology and visual function in addition to maintenance of oxygen homeostasis in outer retina. Our prior studies have confirmed the production of hemoglobin by RPE, however the functional significance of RPE-generated hemoglobin has not been demonstrated. There is no live animal model available that allows for the study of non-erythroid (RPE)-generated hemoglobin independent of that generated by erythroid cells. The proposed study seeks to develop one. Specifically, we will generate a humanized conditional globin gene knockout mouse, a model that expresses human hemoglobin in all hemoglobin-expressing cell types except RPE. The consequences of the absence of hemoglobin in RPE in this model will provide invaluable information regarding the function of RPE-hemoglobin under normal conditions. Additionally, the novel animal model to be generated, a humanized conditional hemoglobin knockout mouse, will be made readily available to the broader research community as a tool to study the cell-type specific significance of hemoglobin.
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