Project: Research project

Project Details


The goal of this study is to determine how mutations in ribosomal proteins alter mRNA translation in Diamond-Blackfan anemia (DBA). Ribosomal protein mutations, either congenital or somatically acquired, are the causes of some human hematological disorders with manifestations of ineffective erythropoiesis and bone marrow failure. For example, Rps19 haploinsufficiency from congenital mutations cause DBA. Although the detailed molecular mechanisms underlying the pathogenesis of DBA are still not clear, two observations argue that altered translational programs may contribute to DBA. First, Rps19 mutated cells have reduced global translation. Second, erythropoiesis is particularly sensitive to perturbations on the translational apparatus. Indeed, a recent study on a DBA case indicated that mutations in Rps19 could lead to altered translation of Gata1 mRNA, which encodes a critical transcription factor in erythropoiesis. This mRNA-specific translation change results in ineffective erythropoiesis in DBA. Thus, determining how the DBA-associated ribosomal protein mutations (e.g., Rps19 haploinsufficiency) change translational regulation programs will provide insights into how dysregulation of mRNA translation contributes to ineffective erythropoiesis. We plan to use ribosome profiling to determine how three novel forms of translational regulations we recently uncovered in normal erythropoiesis (widespread usage of upstream open reading frames, alternative translation terminations, and stoichiometric synthesis of protein complexes) are altered in DBA-mimic erythroid cells. We believe the results from this study may identify therapeutic targets for DBA and other human hematological disorders caused by ribosomal protein mutations, such as Shwachman-Diamond syndrome and 5q-syndrome.

Effective start/end date7/1/186/30/20


  • Congressionally Directed Medical Research Programs: $500,850.00


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