Summary
This research project aims to investigate the underlying mechanisms of severe delayed hemolytic transfusion reaction (DHTR) and hyperhemolysis in sickle cell disease (SCD), focusing on the role of type I interferon (IFN-I) in red blood cell (RBC) destruction and impaired erythropoiesis, to identify biomarkers and develop novel therapeutic strategies.
What they want
The project involves two main aims. Aim 1 focuses on identifying mechanisms of bystander hemolysis by examining the role of key phagocytosis activation molecules like thrombospondin (TSP-1) and its ligands, comparing antibody (Ab)-mediated versus Ab-independent RBC engulfment, and interrogating FcγR/SYK and heme activation pathways. It will also examine IFN-I as a biomarker for DHTR severity using SCD patient samples. Aim 2 will define the mechanisms by which IFN-I suppresses erythropoiesis using primary erythroid cell cultures, human erythroblast cell lines, and mouse models. This aim will also test the therapeutic effects of inhibiting IFN-I production/signaling or increasing EPO/EPOR signaling to reverse impaired bone marrow erythropoiesis.
Deliverables
- Identification of mechanisms of bystander hemolysis
- Understanding the role of phagocytosis activation molecules (e.g., thrombospondin (TSP-1) and its ligands)
- Comparison of Ab-mediated erythrophagocytosis versus Ab-independent RBC engulfment
- Interrogation of murine/human FcγR/SYK pathway and heme activation pathways in bystander hemolysis
- Evaluation of IFN-I as a biomarker of DHTR severity in SCD patient samples
- Definition of mechanisms by which IFN-I suppresses erythropoiesis
- Testing of therapeutic effects of inhibiting IFN-I production/signaling or increasing EPO/EPOR signaling on erythropoiesis
- Potential stratification of risk for DHTR severity
- Aid in development of novel targeted therapies to reverse or prevent hyperhemolysis
