Genetic Dissection of Stress Responses in Shwachman-Diamond Syndrome - (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.
