DEVDBA: Ontogeny as a critical determinant of DBA sensitivity in red blood cells

Ribosomes are the essential molecular machines that translate the genetic code into proteins in our cells. Mutation in the component ribosomal proteins can cause diseases, termed ribosomopathies, of which the best known is Diamond-Blackfan Anemia (DBA), which affects the production of red blood cells (RBCs). RBCs are the most abundant cell type in the body and an essential component for life. Thus, RBCs are constantly produced throughout embryonic, fetal and postnatal life. However, DBA patients present hematological symptoms and die from anemia if not treated only after birth, indicating that only RBCs produced postnatally are sensitive to DBA mutations. Our goal is to understand what determines the difference in sensitivity to a DBA mutation across the different RBCs produced before and after birth. We hypothesize that impaired RBC production observed after birth may be caused by altered ribosome availability or by the acquisition of a developmental-specific ribosome repertoire (i.e. a “ribosome code”) postnatally. To distinguish between these possibilities, We will generate embryonic, fetal and adult RBC from human embryonic stem cells carrying DBA mutations in which we will compare potential changes in ribosome composition and function. This genetically tractable system will allow us to address the dynamics and potential functional role of specialized ribosomes during RBC development. Our combined expertise will identify lineage-specific “translational targets”, which will be tested as novel targeted therapeutic avenues for patients affected by DBA.