Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease characterized by exocrine pancreatic insufficiency, bone marrow failure, increased risk of acute myeloid leukemia, and other variable developmental abnormalities. The molecular mechanisms underlying the pathogenesis of SDS are currently unknown. The SDS gene (named SBDS) is predicted to encode a highly conserved, novel protein of unknown function that is ubiquitously expressed throughout human tissues. SBDS has been postulated to function in RNA processing based on indirect evidence in orthologues. We have established and characterized cell lines from a series of SDS patients followed at Children's Hospital and have generated an antibody against the SBDS protein. In project 1, we will investigate SBDS protein function using three experimental approaches: A. Immunoprecipitation of the SBDS protein complex to identify associated protein binding partners; B. Identification of the regulatory factors controlling the intracellular localization of SBDS; and C. Investigation of the postulated role of SBDS in RNA processing by assessing SBDS RNA binding, association with ribonucleoprotein complexes, and ribosomal RNA maturation. Project 2 involves the characterization of the cellular phenotype of SBDS-/- cells. Biochemical processes regulating cell cycle progression, apoptosis, and response to genotoxic and cellular stressors will be interrogated. All cellular SDS phenotypes will be validated by assaying for genetic rescue following the introduction of the wild-type SBDS cDNA. The identification of a cellular SDS phenotype will provide a functional assay with which to assess any SBDS-interacting proteins identified in Project 1. In Project 3, SBDS function in development and disease will be studied by generating an SBDS-/- mouse. SDS thus provides a disease model to study fundamental molecular processes contributing to marrow failure and leukemogenesis.
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