Summary
This research project aims to investigate how erythroblastic island macrophages (EBI Mφ) contribute to disordered erythropoiesis in Sickle Cell Disease (SCD) by examining the mechanisms of impaired EPO/EPOR signaling, inflammation, and growth factor production.
What they want
The project will define mechanisms for increased CCL/CXCL16 production by EBI Mφ and their role in impaired erythroid progenitor proliferation in SCD, hypothesizing that hemolysis-mediated TLR4/NFkB activation inhibits the EPO/EPOR-PPARγ axis. It will also define mechanisms and contributions of decreased IGF1/SCF production by EBI Mφ to impaired erythroid progenitors due to hemolysis-driven inhibition of EPO/EPOR signaling. Furthermore, the research will define mechanisms and the role of defective phagocytotic ability of EBI Mφ in impaired enucleation in SCD, hypothesizing that hemolysis-driven inhibition of EPO/EPOR-PPARγ signaling diminishes their ability to engulf extruded nuclei. Lastly, it will define mechanisms and contribution of defective efferocytosis by EBI Mφ to impaired erythropoiesis, hypothesizing that decreased efferocytosis due to hemolysis-driven inhibition of EPO/EPOR signaling contributes to an inflammatory BM environment. Therapeutic potential of transfusions, hemopexin, and PPARγ agonists will be examined across all aims.
