Genetic Dissection of Stress Responses in Shwachman-Diamond Syndrome

(请保存在Word中，不要保存为PDF) 在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 一个代谢活跃的细胞含有多达107个核糖体，这些核糖体由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，效率和保真度极高。编码核糖体组装或功能的成分或调节器的基因的种系或体细胞缺陷会导致核糖体疾病，这种疾病发生在儿童和成人患者中。Shwachman-Diamond综合征(SDS)是一种典型的核糖体疾病。本病以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为特征。SBDS的遗传消融导致小鼠早期胚胎死亡(ED6.5)。斑马鱼SBDS蛋白与人类同源基因有90%的同源性。我们创造了具有表型复制的SBDS、Efl1和Eif6斑马鱼基因敲除菌株。基于对人类和鱼类组织的生化和遗传分析，我们假设SBDS的丢失是由于EIF6的积累和随后的异常代谢导致的疾病。当这些生化反应过度时，代谢缺陷、生长停滞、细胞死亡和组织萎缩就会随之而来。最初是适应性的，TP53突变可能会变得不适应。利用现有的斑马鱼、细胞系和患者来源的组织以及既定的方法，我们提出了以下特定的目标来解决我们的假设：确定EIF6积累的细胞间隔室，并表征其对可能参与SDS发病机制的代谢途径的影响。我们的长期目标是更多地了解核糖体疾病是如何导致人类疾病的，并转化新的生物医学知识来改善那些患有抑郁症的人的生活质量。

(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.