Genetic Dissection of Stress Responses in Shwachman-Diamond Syndrome

什瓦赫曼-戴蒙德综合征应激反应的基因剖析

基本信息

批准号：
10594366
负责人：
Seth Joel Corey
金额：
$ 24.15万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-22 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594366
关键词：
Ablation Address Adult Affect Alleles Amino Acids Atrophic Biochemical Biology Blood Bone marrow failure CRISPR/Cas technology Cell Death Cell Line Cell Nucleolus Cell physiology Cells Childhood Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytoplasm DNA Repair Defect Disease Dissection Embryo Eukaryotic Cell Exocrine pancreatic insufficiency Experimental Designs Fertilization Fishes Functional disorder G6PC3 gene Generations Genes Genetic Goals Growth Health Hematopoiesis Human Human Cell Line Investigation Knock-out Knowledge Lead Maintenance Metabolic Metabolic Pathway Metabolic stress Metabolism Methods Modeling Molecular Mus Mutate Mutation Myelogenous Neoplasms Neutropenia Nutrient Orthologous Gene Pancreas Pathogenesis Pathway interactions Patients Phenocopy Phenotype Polyribosomes Process Production Protein Biosynthesis Proteins Quality of life RNA Recommendation Ribosomes Risk Shwachman-Diamond syndrome Somatic Mutation Stress Survival Rate Syndrome TP53 gene Text Tissues Translating Validation Western Blotting Zebrafish autosome biological adaptation to stress bone marrow failure syndrome cancer predisposition cell behavior chromosome 20q loss genetic analysis human disease improved innovation lipid metabolism model organism mutant neutrophil novel novel therapeutics pressure protein metabolism prototype recruit response ribosomopathy skeletal dysplasia

项目摘要

(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.

（请保持言语，不要PDF）在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。代谢活性细胞包含多达107个核糖体，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，效率极高和保真度。编码核糖体组件或功能调节剂的基因中的生殖线或体细胞缺陷会导致核糖体病，这发生在小儿和成年患者中。 Shwachman-Diamond综合征（SDS）是一种原型核糖瘤病。 SDS的特征是外分泌胰腺功能不全，中性粒细胞减少症，骨骼发育不良和身材矮小。 SBD的遗传消融导致小鼠早期胚胎致死性（ED 6.5）。斑马鱼SBD蛋白与人类直系同源物相同。我们创建了SBD，EFL1和EIF6斑马鱼敲除菌株，这些敲除SDS。基于人类和鱼类组织的生化和遗传分析，我们假设SBD的丧失由于EIF6的积累和随后的异常代谢而产生疾病。当这些生化反应过多时，随之而来的是代谢缺陷，生长停滞，细胞死亡和组织萎缩。最初自适应，TP53突变可能成为适应不良的。使用可用的斑马鱼，细胞系和患者衍生的组织以及已建立的方法，我们提出了以下特定目的来解决我们的假设：确定EIF6积累的细胞区室，并表征其对代谢途径的影响，这可能有助于SDS的发病机理。我们的长期目标是获得有关核糖病如何引起人类疾病并翻译新的生物医学知识以改善患者（尤其是SDS）的生活质量的知识。