(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes, such as limb and craniofacial defects as well as bone marrow failure. A key example of a ribosomopathy is Diamond Blackfan Anemia (DBA) which results in an erythroid-specific disease manifestation. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Our preliminary data strongly support that translational dysfunction may contribute to disease pathogenesis. In particular, our findings show that translational specificity to gene expression upon ribosomal protein (RP) haploinsufficiency may arise from an intermediary pathway, the p53-4EBP1-eIF4E axis, which becomes activated and links RP haploinsufficiency to selective changes in cap-dependent translation, namely mRNAs with structured 5’UTRs that require eIF4A helicase activity or that have a specific sequence element. This preliminary data strongly supports the rationale to examine translational control and protein synthesis within the hematopoietic compartment, which has been previously unattainable to resolve and has limited our understanding of DBA pathogenesis. In Aim 1, we will delineate the function of 4EBP1 in controlling transcript-specific translational control that may underlie DBA pathogenesis. In particular, we will define whether 4EBP1 mediated translation of long, structured 5’UTRs is impaired upon RP haploinsufficiency and may underlie DBA pathogenesis. In Aim 2, we will characterize a novel small molecule that upregulates general protein synthesis as a means for restoring the translational landscape of DBA. In particular, we will define how a semi-synthetic macrolide antibiotic, Azithromycin, that we have already identified in a large chemical screen acts as a translation activator. We will also test the effects of Azithromycin in rescuing the pathogenesis of DBA in human stem cell models of the disease. Together, this proposal holds the potential to transform our understanding and treatment of an entire class of human diseases.