Biochemical and Molecular Analysis of Shwachman-Diamond Syndrome

描述(申请人提供)：Shwachman-Diamond综合征(SDS)是一种常染色体隐性遗传病，会导致造血缺陷以及胰腺功能和骨骼发育受损。目前，治疗选择仅限于支持性护理或骨髓移植，这有严重并发症的风险。该项目的目标是通过阐明SDBS的功能来解决这一重要问题，SDBS是一种基因，当突变时会导致SDS，并确定可能有助于理解和治疗该病的小分子药物。我们将开发一个酿酒酵母模型系统来进行我们的研究，我们对SBDS的酵母同源基因SDO1(Shwachman-Diamond Orolog 1)的分子功能的初步表征揭示了它在核糖体生物发生中的作用。此外，我们还发现SDO1的缺失会导致生长缓慢，这种表型可以用于高通量筛选目的。在这里，我们建议研究SDO1在核糖体生物发生中的作用，特别是rRNA的加工、转录和修饰。此外，我们将使用酵母分子方法来鉴定在最近完成的高通量小分子筛查中获得的HITS，并识别最有趣的HITS的蛋白质靶标。综上所述，这项工作将阐明SDO1的功能。此外，这一努力将为深入了解SDS以及调节骨髓功能和造血的分子机制提供重要的见解。公共卫生相关性：该提案将阐明SDO1的功能，并确定可用于理解和潜在治疗抑郁症的小分子。因此，我们期望这一努力的结果将大大有助于我们对骨髓功能和造血的理解。

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.