Genetic Dissection of Stress Responses in Shwachman-Diamond Syndrome

（请保持文字，不要PDF） 在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 一个具有代谢活性的细胞含有多达107个核糖体，它们由RNA和蛋白质组成。这些复杂的生化机器以每分钟200个氨基酸的速度合成蛋白质，具有极高的效率和保真度。编码核糖体组装或功能的组分或调节剂的基因中的种系或体细胞缺陷引起核糖体病，其发生在儿科和成人患者中。Shwachman-Diamond综合征（SDS）是一种典型的核糖体病。SDS的特征是胰腺外分泌功能不全、中性粒细胞减少、骨骼发育不良和身材矮小。Sbds的基因消除导致小鼠早期胚胎死亡（艾德6.5）。斑马鱼Sbds蛋白与人类直系同源物约90%相同。我们创建了sbds，efl 1和eif 6斑马鱼敲除菌株，表型SDS。基于对人类和鱼类组织的生化和遗传分析，我们假设SBDS的缺失由于EIF 6积累和随后的异常代谢而产生疾病。当这些生化反应过度时，随之而来的是代谢缺陷、生长停滞、细胞死亡和组织萎缩。最初的适应性，TP 53突变可能变得适应不良。使用现有的斑马鱼，细胞系，和患者来源的组织和建立的方法，我们提出了以下具体目标，以解决我们的假设：确定EIF 6积累的细胞隔室，并表征其对代谢途径的影响，可能有助于SDS的发病机制。我们的长期目标是获得更多关于核糖体病如何导致人类疾病的知识，并将新的生物医学知识转化为改善受影响者的生活质量，特别是SDS。

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. A metabolically active cell contains as many as 107 ribosomes, which are composed of RNA and protein. These complex biochemical machines synthesize proteins at a rate of 200 amino acids per minute with extremely high efficiency and fidelity. Germline or somatic defects in genes encoding components or regulators for ribosome assembly or function cause ribosomopathies, which occur in pediatric and adult patients. Shwachman-Diamond syndrome (SDS) is a prototypic ribosomopathy. SDS is characterized by exocrine pancreatic insufficiency, neutropenia, skeletal dysplasia, and short stature. Genetic ablation of Sbds results in early embryonic lethality (ED 6.5) in mice. The zebrafish Sbds protein is ~90% identical to the human ortholog. We created sbds, efl1, and eif6 zebrafish knockout strains that phenocopy SDS. Based on biochemical and genetic analysis of human and fish tissues, we hypothesize that the loss of SBDS produces disease due to EIF6 accumulation and subsequent aberrant metabolism. When these biochemical responses are excessive, metabolic defects, growth arrest, cell death, and tissue atrophy ensue. Initially adaptive, TP53 mutations may become maladaptive. Using available zebrafish, cell lines, and patient-derived tissues and established methods, we propose the following specific aim to address our hypothesis: Identify the cellular compartment for EIF6 accumulation and characterize its effects on metabolic pathways that could contribute to the pathogenesis of SDS. Our long-term goals are to gain greater knowledge on how ribosomopathies cause human disease and translate new biomedical knowledge to improve the quality of life for those afflicted, particularly SDS.