Rare disorders offer unique insights into global pathologic mechanisms affecting the general population. The study of inherited bone marrow failure syndromes has elucidated novel molecular pathways underlying hematopoietic aplasia and cancer predisposition. Genetic mutations affecting ribosome biogenesis underlie several inherited bone marrow failure syndromes: Diamond-Blackfan anemia, dyskeratosis congenita, cartilage-hair hypoplasia, and Shwachman-Diamond syndrome. More recently, acquired haploinsufficiency of the RPS14 gene has been associated with the 5q- myelodysplastic syndrome. It is currently unclear how ribosomal disorders result in marrow failure and leukemogenesis. To investigate the role of ribosomes in hematopoiesis and malignancy, we focused on Shwachman- Diamond syndrome, an autosomal recessively inherited marrow failure syndrome associated with mutations in the highly conserved SBDS gene. The precise molecular functions of SBDS in ribosomal pathways remain to be defined. Based upon our prior studies, we propose the following specific aims: 1. Define the functional domains of the SBDS protein, 2. Investigate the molecular mechanisms whereby SBDS promotes ribosome biogenesis, and 3. Elucidate the role of SBDS in hematopoiesis.
These studies stand to advance our understanding of how ribosomal abnormalities contribute to aplastic anemia and leukemia and to identify novel therapeutic targets.
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