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Mechanisms regulating ribosome assembly and function in stem cells and vertebrate development.

干细胞和脊椎动物发育中核糖体组装和功能的调节机制。

基本信息

批准号：
10627849
负责人：
Eliezer Calo-Velazquez
金额：
$ 37.42万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2026-05-31
项目状态：
未结题

项目摘要

Protein synthesis underpins a cell’s decision to growth, proliferate and/or differentiate.2,6,11–14,14,15,18 Understanding how protein synthesis allow cells to perform these fundamental activities is a major challenge in biology. Therefore, there is a critical need to elucidate the mechanisms determining protein synthesis rates and whether these mechanisms operate in a cell type-specific manner to impart a new layer of regulation in the control of gene expression. To explore these questions, two orthogonal, but complementary, research programs, namely Program 1 and 2, have been designed. Program 1 investigates new factors and mechanisms involved in the regulated assembly of ribosomes in stem cells. Program 1 is built upon recent studies from my lab and others demonstrating that stem cells relies on ribosome assembly to ensure adequate protein synthesis rates and the transition from self-renewal to differentiation.2,3,6,11–14,14,15,18 My lab has characterized the composition of the small subunit (SSU) processome in human cells, and identified DNA-dependent protein kinase (DNA-PK) as an RNA-dependent regulator of ribosome assembly and proteins synthesis in hematopoietic stem cells.6 Thus, the immediate goal of Program 1 is to establish the mechanisms by which DNA-PK regulates ribosome biogenesis in stem cells. Program 2 explores how customizing ribosome assembly and function contributes to protein synthesis and selective mRNA translation during embryogenesis. Program 2 is underscored by recent findings suggesting that ribosomes composition and activity are dynamically regulated in a cell type- and tissue- specific manner, allowing protein expression to be regulated with exquisite temporal and spatial precision.8,12 The immediate goal of Program 2 is to generate in vivo model systems to understand how the cell creates and regulates ribosome heterogeneity and the importance of this form of regulation for proper cellular function and organismal development. To address these, we have generated transgenic zebrafish in which two compositionally distinct and developmentally regulated ribosomes have been genetically labeled, a unique and powerful tool to study functional aspects of the ribosome in an in vivo developmental model system. Over the next five years, we expect Program 1 and 2 to uncover new mechanisms regulating ribosomes assembly and function in stem cells and vertebrate development and to provide powerful insights into ribosomopathies, tissue- specific disorders linked to defects in ribosome biogenesis and function.

蛋白质合成是细胞决定生长、增殖和/或分化的基础。理解蛋白质合成如何允许细胞执行这些基本活动是一项重大挑战生物学。因此，迫切需要阐明决定蛋白质合成速率和蛋白质合成速率的机制。这些机制是否以特定于细胞类型的方式运行，以在基因表达的控制。为了探索这些问题，两个相互垂直但互补的研究计划，即方案1和方案2已经设计完成。方案1调查涉及的新因素和新机制在干细胞中核糖体的调节组装中。计划1建立在我实验室的最新研究基础上其他人证明干细胞依赖核糖体组装来确保足够的蛋白质合成率以及从自我更新到差异化的转变。2，3，6，11-14，14，15，18我的实验室已经表征了人细胞中的小亚基(SSU)过程，并鉴定出DNA依赖的蛋白激酶(DNA-PK)是一种依赖于RNA的造血干细胞核糖体组装和蛋白质合成的调节因子。程序1的直接目标是建立DNA-PK调节核糖体的机制干细胞的生物发生。计划2探索定制核糖体组装和功能如何有助于胚胎发育过程中的蛋白质合成和选择性信使核糖核酸的翻译。计划2由最近的研究结果表明，核糖体的组成和活性在一种细胞类型和组织中受到动态调节特定的方式，允许以精细的时间和空间精度调节蛋白质的表达。8，12 程序2的直接目标是生成体内模型系统，以了解细胞是如何创建和调节核糖体异质性以及这种形式的调节对正常细胞功能和生物体发育。为了解决这些问题，我们培育了转基因斑马鱼，其中两种成分独特且受发育调节的核糖体已被基因标记，一种独特的在体内发育模型系统中研究核糖体功能的有力工具。超过了未来五年，我们预计计划1和计划2将发现调节核糖体组装和在干细胞和脊椎动物发育中的作用，并提供对核糖体疾病、组织- 与核糖体生物发生和功能缺陷相关的特定疾病。