TO REPAIR OR TO DIE: THE CELLULAR RESPONSE TO RIBOSOMOPATHY-CAUSING MUTATIONS

修复或死亡：细胞对核糖体病引起的突变的反应

• 批准号: MR/W017881/1
• 负责人: Jean-Paul Vincent
• 金额: $ 61.86万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW017881%2F1
• 关键词: REPAIR; DIE; CELLULAR; RESPONSE; RIBOSOMOPATHY

Proteins, a diverse set of molecules that are essential for life, are made up of building blocks (amino acid), assembled in a sequence dictated by genes. Genes direct the production of messenger RNA which are then used as a template for protein synthesis by sophisticated nanomachines called ribosomes. In the absence of ribosomes, e.g. when one of their 83 constituents is missing, life cannot be sustained. Partial ribosome deficiency, e.g. when one constituent is defective or in reduced amount, can often be tolerated, although it is associated with a variety of diseases collectively known as ribosomopathies. These encompass a large number of syndromes that each affect predominantly specific tissues such as the blood, bones, the brain and more. It has been assumed that these symptoms stem largely from the cells' inability to produce sufficient protein. We found however that, in an animal model of ribosomopathy, cells display many markers of cellular stress that is normally caused by the accumulation of defective proteins. We have suggested that the need to remove defective ribosomes overwhelms the cellular machinery that normally destroys other defective proteins. Thus, defective proteins accumulate, impairing the cell's activity, much like interruptions of curb-side waste collection affect city life. Within a ribosome-deficient tissue, some cells undergo apoptosis (a form of cell suicide), while others survive and learn to live with chronic stress. We are proposing to use our animal model as well as cells from patients to decipher the molecular machinery that detects the presence of defective ribosomes and controls the decision between cell death and repair. By understanding the molecular pathways that cells activate in response to defective ribosomes, we will infer ways to boost their protective response, especially in neurons, a type of cells that are particularly sensitive to the presence of defective proteins. We expect that our results will open up new therapeutic avenues to alleviate the symptoms of ribosomopathies and possibly other proteinopathies.

蛋白质是一组对生命至关重要的不同分子，由构建模块（氨基酸）组成，按基因规定的顺序组装。基因指导信使RNA的产生，信使RNA随后被称为核糖体的复杂纳米机器用作蛋白质合成的模板。在核糖体缺失的情况下，例如当83种核糖体中的一种成分缺失时，生命就无法维持。部分核糖体缺乏，例如当一种成分有缺陷或数量减少时，通常是可以容忍的，尽管它与统称为核糖体病的各种疾病有关。这些包括大量的综合症，每种综合症主要影响特定的组织，如血液、骨骼、大脑等。据推测，这些症状主要源于细胞无法产生足够的蛋白质。然而，我们发现，在核糖体病的动物模型中，细胞显示出许多通常由缺陷蛋白积累引起的细胞应激标记。我们已经提出，需要去除有缺陷的核糖体压倒了通常破坏其他有缺陷蛋白质的细胞机制。因此，有缺陷的蛋白质积累，损害细胞的活动，就像路边垃圾收集的中断影响城市生活一样。在缺乏核糖体的组织中，一些细胞发生凋亡（细胞自杀的一种形式），而另一些细胞存活下来并学会忍受慢性压力。我们建议使用我们的动物模型以及来自患者的细胞来破译检测缺陷核糖体存在并控制细胞死亡和修复之间决定的分子机制。通过了解细胞对缺陷核糖体的反应激活的分子途径，我们将推断出增强其保护反应的方法，特别是在神经元中，这是一种对缺陷蛋白质的存在特别敏感的细胞。我们期望我们的结果将开辟新的治疗途径，以减轻核糖体病和其他可能的蛋白质病的症状。