Role of CYB5R3 in erythropoiesis - grant title: role of CYB5R3 in erythropoiesis funding mechanism: NIH/nhlbi-F32 project summary/abstract cytochrome B5 reductase 3 (CYB5R3) plays a critical role in…

The National Heart Lung and Blood Institute awarded the University of Pittsburgh $158,600 on December 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to support mentored postdoctoral research investigating the role of cytochrome B5 reductase 3 (CYB5R3) in erythropoiesis through December 31, 2027.

The research examines CYB5R3's previously unexplored function in regulating heme biosynthesis and red blood cell production, with potential applications in drug development and management of genetic anemias including sickle cell disease. The CYB5R3 T117S variant reduces reductase activity by approximately 50% and modifies the hematologic response to hydroxyurea, a widely used therapeutic for sickle cell anemia. The study comprises two specific aims: investigation of CYB5R3 depletion's impact on hemoglobin synthesis and erythropoiesis using human K562 cells, and assessment of effects on erythropoiesis in vivo using a novel mouse model with hematopoietic compartment-specific CYB5R3 deletion under baseline and hypoxic conditions. The research plan includes mentored training under established faculty investigators. Work is performed in Pittsburgh, Pennsylvania.

Role of CYB5R3 in erythropoiesis - grant title: role of CYB5R3 in erythropoiesis funding mechanism: NIH/nhlbi-F32 project summary/abstract cytochrome B5 reductase 3 (CYB5R3) plays a critical role in regulating redox signaling in both physiological and pathological contexts. Key biological substrates of CYB5R3 include hemoproteins such as hemoglobin, myoglobin, and soluble guanylate cyclase (SGC), as well as vitamin E and coenzyme Q. Our recent findings demonstrate that the CYB5R3 T117S variant, which results in approximately 50% loss of reductase activity, serves as a modifier of hydroxyurea-induced fetal hemoglobin (HBF) production-a widely used therapeutic approach for managing anemia in sickle cell disease (SCD). Using CYB5R3 knockout CD34+ hematopoietic stem cells (HSC)S, we found depleted baseline hemoglobin and impaired hydroxyurea- induced HBF production and erythroid maturation. In CYB5R3-deleted human erythroleukemic K562 cells, we similarly found depleted baseline hemoglobin, but in the presence of heme deficiency. The role of CYB5R3 in erythropoiesis remains unexplored despite. Based on our preliminary and published data, we hypothesize that CYB5R3 plays a previously unrecognized role in erythropoiesis by regulating heme biosynthesis. This hypothesis will be tested using two specific aims: aim 1 will investigate the impact of CYB5R3 depletion on hemoglobin synthesis and erythropoiesis using human K562 cells. Aim 2 will employ a novel mouse model with hematopoietic compartment-specific deletion of CYB5R3 to assess its effects on erythropoiesis in vivo, both under baseline conditions and following hypoxic conditions. Successful completion of this study will provide novel insights into the significance of CYB5R3 in erythropoiesis, with potential applications in drug development, regenerative medicine, and the improved management of genetic anemias. Moreover, this research-plan combined with mentored training under DRS. Straub and wood, interdisciplinary collaborations, and a structured career development plan within the outstanding training environment at the university of pittsburgh school of medicine-will equip the applicant with the expertise necessary to achieve a long-term career in biomedical research.