Studies of mRNA Translational Regulations in Diamond Blackfan Anemia

Red blood cells (RBCs) are essential to humans, and malfunction of RBC production can cause severe anemia. Importantly, ineffective production of RBCs is associated with a significant number of human hematological disorders, including many bone marrow failure syndromes. Thus, characterizing regulations in RBC production is of both biological and clinical significance. Our recent studies determined three novel forms of regulations in protein synthesis during normal RBC production. Whether these newly identified regulations are altered or contribute to hematological disorders, however, is still unknown. Interestingly, human genetic studies indicate that mutations in the cellular machinery of protein production are the cause of several hematological disorders, such as Diamond Blackfan anemia, which are manifested as bone marrow failure. Thus, we hypothesize that dysregulation of protein synthesis contributes to these hematological disorders. In this study, we will use the ribosomal mutation (Rps19) in Diamond Blackfan anemia as a model to determine how regulations of protein synthesis, particularly the three novel forms of regulations we recently identified, are altered in this disease. We believe the results from this study may identify new therapeutic targets for Diamond Blackfan anemia and other human hematological disorders caused by ribosomal protein mutations, such as Shwachman-Diamond syndrome and 5q-syndrome.