Cellular and Molecular Control of Normal and Disordered Erythropoiesis

Project Summary/Abstract Red cell disorders affect more than 1 billion people worldwide, are a significant cause of morbidity and mortality and lead to a substantial economic burden. These disorders can result from a decrease in survival or in production (or both). Our research is focused on erythropoiesis and how this process goes awry in disorders such as Diamond Blackfan anemia (SCD), sickle cell disease (SCD) and anemia of inflammation. Our work has highlighted differences between neonatal and adult human erythropoiesis and used these findings to reveal the mechanism of steroid resistance in DBA. In parallel, we studied the mechanism of action of immunomodulatory drugs during erythropoiesis and how they increase fetal hemoglobin production in SCD. We recently identified the nature of the erythroblastic island in normal erythropoiesis and under inflammatory conditions. Together, these discoveries have allowed for a better understanding of normal and disordered erythropoiesis. Nevertheless, critical basic and translational questions remain in DBA and SCD. The proposed research program builds upon Dr. Blanc’s productive research track record to determine (i) why the erythropoietic defect in DBA manifests after birth, (ii) how the erythroblastic island in the bone marrow contributes to the pathophysiology of DBA and SCD and (iii) identifying new targets and treatments for DBA and SCD. To answer these questions, we propose an ambitious research program divided into three projects. The first will investigate the impact of differential regulation of ribosome biogenesis and cell cycle length in fetal versus adult erythropoiesis. The second will address the contribution of the newly characterized erythromyeloblastic island to the pathophysiology of DBA and SCD and the third will focus on identifying and testing new drugs for the treatment of these two hematologic disorders. As a whole this program should (i) offer new models to study ribosomal protein biology relevant to heart and blood disorders, (ii) explain how the erythroid niche universally contributes to inflammation in hematologic disorders and (iii) offer new therapies for the treatment of bone marrow failure syndromes and sickle cell disease.