Ribosomes and growth regulation.

核糖体负责细胞内蛋白质的合成，对生长和细胞是必不可少的。 组织。干扰核糖体生物发生的基因缺陷会减少翻译和生长 并导致人类疾病。多种核糖体蛋白基因杂合性突变引起 钻石-布莱克凡贫血，与早发性贫血、形态缺陷、 以及癌症的易感性。核糖体蛋白基因在果蝇中也是单倍体不足的 果蝇，它们导致蛋白质合成减少，生长和发育缓慢，以及 形态缺陷。出乎意料的是，这些影响被发现具有转录基础，即 核糖体蛋白突变激活一个转录程序，该程序控制翻译和 另一种影响。该项目将确定核糖体生物发生缺陷如何导致人类 疾病和癌症通过阐明这种转录反应的分子机制 果蝇，以及利用突变来阻止细胞对核糖体蛋白突变发生反应。 该项目将使用核糖体分析方法来定义步骤的层次结构， 基因组到蛋白质的翻译发生了变化，并突出了那些可能与 癌症、贫血和形态。该项目将使用基因修改方法来定义 个别蛋白质异构体和结构域在核糖体作用中的特殊作用 生物发生缺陷。该项目将探索哪些生理和选择性的作用是由 细胞对核糖体生物发生缺陷的反应及其对促进健康的贡献 生存和预防疾病。预计这一发现将为我们提供 预防癌症和治疗核糖体疾病钻石黑粉贫血。

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.