Biochemical and Molecular Analysis of Shwachman-Diamond Syndrome

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DESCRIPTION (provided by applicant): Shwachman-Diamond Syndrome (SDS) is an autosomal recessive genetic disease that results in hematopoietic defects as well as impaired pancreatic function and skeletal development. Presently, therapeutic options are limited to supportive care or bone marrow transplant, which carries a risk of serious complications. The goal of this project is to address this important problem by elucidating the function of SDBS, the gene which, when mutated, results in SDS, and to identify small molecule pharmaceutics that may be useful for understanding and treating the disease. We shall exploit a Saccharomyces cerevisiae model system for our studies and our initial characterization of the molecular function of SDO1 (Shwachman- Diamond Ortholog 1), the yeast ortholog of SBDS, has revealed that it plays a role in ribosome biogenesis. In addition, we have found that deletion of SDO1 results in slow growth, and that this phenotype can be exploited for high throughput screening purposes. Here, we propose to investigate the role of SDO1 in ribosome biogenesis, in general, and rRNA processing, transcription, and modification, in particular. In addition, we shall employ yeast molecular methods to characterize hits obtained in a recently completed high throughput small molecule screen, and to identify the protein targets of the most interesting hits. Taken together, this work shall elucidate the function of SDO1. In addition, this effort shall provide important insights into SDS, and into the molecular mechanisms mediating bone marrow function and hematopoiesis. Public Health Relevance: This proposal shall elucidate the function of SDO1, and identify small molecules that can be used to understand and potentially treat SDS. We expect that the results of this effort shall therefore contribute significantly to our understanding of bone marrow function and hematopoiesis.