Translational Control: Discovery and Mechanisms

翻译控制：发现和机制

• 批准号: 10623926
• 负责人: Andrei Korostelev
• 金额: $ 64.53万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623926
• 关键词: Address; Amyotrophic Lateral Sclerosis; Antibiotics; Bacteria; Bacterial Infections; Biochemical; Brain; Cell Nucleus; Cellular Stress; Complex; Cryoelectron Microscopy; Disease; Environment; Eukaryota; Gene Expression; Genetic; Genetic Diseases; Genetic Transcription; Human; In Vitro; Learning; Messenger RNA; Methods; Molecular; Movement; Neuronal Plasticity; Neurons; Nonsense Codon; Pathway interactions; Positioning Attribute; Process; Protein Biosynthesis; Proteins; Proteome; Resolution; Ribosomal Interaction; Ribosomes; Stress; Synapses; Synaptic plasticity; Time; Transcriptional Regulation; Translational Regulation; Translations; Visualization; biological adaptation to stress; memory consolidation; nervous system disorder; neurodevelopment; novel; premature; therapeutic development; translation factor

Andrei A. Korostelev ABSTRACT Ribosomes are a central hub for controlling gene expression. They not only synthesize proteins, but also regulate bacterial stress responses, human neurodevelopment and synaptic plasticity. Understanding how ribosomes control gene expression requires high-resolution structural and accurate biochemical characterization of ribosome dynamics and interactions, both in vitro and in complex cellular environments. We are uniquely positioned to address these key challenges by investigating the following questions: How do ribosomes regulate bacterial stress responses? In bacteria, ribosomes sense cellular stress via several pathways, which control the transcriptional adaptation to stress. The direct and indirect pathways that couple translation with transcription are promising antibiotic targets. We will dissect the structural and cellular mechanisms of using novel biochemical approaches and ensemble cryo-EM. How do ribosomes sense functional and dysfunctional mRNAs? Translation is a major pathway for sensing problematic mRNAs in eukaryotes, and dysregulation of stress-response mechanisms leads to disease. To determine how the ribosome recognizes dysfunctional mRNAs with premature nonsense codons, we will use cellular, biochemical and structural (time-resolved cryo-EM) methods to visualize ribosome interactions with problematic mRNAs. How does translation regulate neurodevelopment and neuroplasticity and contribute to neurological disorders? Translation regulation in neurons is essential for neurodevelopment, memory consolidation, and learning, whereas translation dysregulation drives neurological diseases, such as amyotrophic lateral sclerosis. The synaptic proteome—far from the nucleus—is controlled by local translation and requires brain-specific translation factors and auxiliary proteins. To elucidate the molecular mechanisms of neuronal translation regulation, we will use genetic, biochemical, and structural approaches, including cellular EM at Ångström-level detail in functional neurons.

安德烈·A·科罗斯捷列夫 抽象的 核糖体是控制基因表达的中心枢纽。它们不仅合成蛋白质，而且还调节 细菌应激反应、人类神经发育和突触可塑性。了解核糖体如何 控制基因表达需要高分辨率的结构和准确的生化特征 体外和复杂细胞环境中的核糖体动力学和相互作用。我们是独一无二的 通过调查以下问题来应对这些关键挑战： 核糖体如何调节细菌应激反应？在细菌中，核糖体通过以下方式感知细胞压力 控制转录适应应激的多种途径。直接和间接途径 翻译与转录的结合是有希望的抗生素靶点。我们将剖析结构和细胞 使用新型生化方法和整体冷冻电镜的机制。 核糖体如何感知功能性和功能失调的 mRNA？翻译是主要途径 感知真核生物中有问题的 mRNA，应激反应机制的失调会导致疾病。 为了确定核糖体如何识别带有过早无义密码子的功能失调的 mRNA，我们将使用 细胞、生化和结构（时间分辨冷冻电镜）方法可视化核糖体与 有问题的 mRNA。 翻译如何调节神经发育和神经可塑性并有助于神经学 失调？神经元的翻译调节对于神经发育、记忆巩固和 学习，而翻译失调会导致神经系统疾病，例如肌萎缩侧索硬化症。 突触蛋白质组远离细胞核，由局部翻译控制，需要大脑特异性 翻译因子和辅助蛋白。阐明神经元翻译的分子机制 调节，我们将使用遗传、生化和结构方法，包括埃格斯特伦水平的细胞 EM 功能神经元的细节。