Biochemical and Molecular Analysis of Shwachman-Diamond Syndrome

描述（由申请人提供）：Shwachman-Diamond综合征（SDS）是一种常染色体隐性遗传疾病，可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是突变时导致SDS的基因，并确定可能有助于理解和治疗该疾病的小分子药物。我们将利用酿酒酵母模型系统进行我们的研究，我们对SDO 1（Shwachman-Diamond Ortholog 1）（SBDS的酵母直系同源物）的分子功能的初步表征表明，它在核糖体生物发生中起作用。此外，我们发现SDO 1的缺失导致生长缓慢，并且这种表型可以用于高通量筛选目的。在这里，我们建议调查的作用，SDO 1在核糖体的生物合成，一般情况下，rRNA加工，转录和修改，特别是。此外，我们将采用酵母分子方法来表征在最近完成的高通量小分子筛选中获得的命中，并确定最感兴趣的命中的蛋白质靶标。总之，这项工作将阐明SDO 1的功能。此外，这项工作将提供重要的见解SDS，并进入介导骨髓功能和造血的分子机制。公共卫生相关性：该提案将阐明SDO 1的功能，并确定可用于理解和潜在治疗SDS的小分子。我们期望，这项工作的结果，因此将有助于显着我们了解骨髓功能和造血。

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.