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Ribosomes and growth regulation.

核糖体和生长调节。

基本信息

批准号：
10661417
负责人：
Nicholas E Baker
金额：
$ 33.6万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-08 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661417
关键词：
5&apos Untranslated Regions Affect Alleles Anemia Antioxidants Autophagocytosis Biogenesis Bioinformatics Biological Assay CRISPR/Cas technology Cancer Etiology Cell division Cell physiology Cells Cultured Cells Cytoprotection DNA Binding Domain DNA Transposable Elements Defect Development Diamond-Blackfan anemia Disease Drosophila genus Gene Modified Gene Proteins Genes Genetic Genetic Transcription Genome Genomic Instability Genotype Growth Growth and Development function Health Promotion Heterozygote Human Impairment Individual Instruction Loss of Heterozygosity Luciferases Malignant Neoplasms Mammals Maps Mediating Messenger RNA Methods Molecular Morphology Mutate Mutation Organism Oxidative Stress Pathway interactions Peptide Initiation Factors Phenotype Phosphorylation Physiological Play Protein Biosynthesis Protein Isoforms Proteins Reaction Regulation Reporter Ribosomal Proteins Ribosomes Role TP53 gene Tertiary Protein Structure Tissues Transcriptional Regulation Transgenes Translating Translational Repression Translations bZIP Domain biological adaptation to stress cancer predisposition deletion analysis early onset fitness fly human disease mRNA Stability mRNA sequencing multicatalytic endopeptidase complex mutant prevent programs response ribosome profiling ribosomopathy sensor transcription factor ubiquitin-protein ligase

项目摘要

Ribosomes are responsible for protein synthesis in the cell and are essential for growth and cell division. Genetic defects that interfere with ribosome biogenesis reduce translation and growth and cause human diseases. Heterozygous mutation of many ribosomal protein genes causes Diamond-Blackfan Anemia, which is associated with early onset anemia, morphological defects, and cancer predisposition. Ribosomal protein genes are also haploinsufficient in the fruitfly Drosophila, where they cause reduced protein synthesis, slow growth and development, and morphological defects. Unexpectedly, these effects are found to have a transcriptional basis, that is, ribosomal protein mutations activate a transcriptional program which controls translation and the other effects. This project will determine how ribosome biogenesis defects cause human diseases and cancer by elucidating the molecular mechanisms of this transcriptional response in Drosophila, and exploiting mutations that prevent cells reacting to ribosomal protein mutations. The project will use ribosome profiling methods to define the hierarchy of steps at which translation of the genome into protein is altered and highlight those likely to be relevant to cancer, anemia, and morphology. The project will use gene modification approaches to define the specific roles of individual protein isoforms and domains in the effects of ribosome biogenesis defects. The project will explore what physiological and selective role is played by the cellular responses to ribosome biogenesis defects, and their contribution to promoting health and survival and preventing disease. The findings are anticipated to suggest approaches to prevent cancer and treat the ribosomopathy Diamond Blackfan Anemia.

核糖体负责细胞中的蛋白质合成，并且是细胞生长和细胞增殖所必需的。师.干扰核糖体生物合成的遗传缺陷会减少翻译和生长导致人类疾病许多核糖体蛋白基因的杂合突变导致 Diamond-Blackfan贫血，与早发性贫血、形态缺陷、和癌症易感性。核糖体蛋白基因在果蝇中也是单倍不足的果蝇，它们会导致蛋白质合成减少，生长和发育缓慢，形态缺陷出乎意料的是，发现这些效应具有转录基础，核糖体蛋白突变激活了一种控制翻译的转录程序，其他影响。该项目将确定核糖体生物合成缺陷如何导致人类通过阐明这种转录反应的分子机制，果蝇，并利用突变，防止细胞反应的核糖体蛋白质突变。该项目将使用核糖体分析方法来定义步骤的层次结构，基因组向蛋白质的翻译被改变，并突出那些可能与癌症贫血和形态学该项目将使用基因修饰方法来定义单个蛋白质异构体和结构域在核糖体作用中的特定作用生物成因缺陷该项目将探讨什么样的生理和选择性的作用，细胞对核糖体生物合成缺陷的反应，以及它们对促进健康的贡献生存和预防疾病。预计这些发现将为以下方面提出建议：预防癌症和治疗核糖体病钻石黑帆贫血。