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Understanding Nuclear RNA Quality Control in Mammalian Nervous System

了解哺乳动物神经系统中的核 RNA 质量控制

基本信息

批准号：
BB/M001199/1
负责人：
Eugene Makeyev
金额：
$ 76.67万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM001199%2F1
关键词：
Understanding Nuclear RNA Quality Control

项目摘要

Expression of our genes proceeds through several carefully orchestrated steps including transcription and processing of primary transcripts into mature messenger molecules, export of the messengers from the nucleus to the cytoplasm and their translation into corresponding protein products. This elaborate process is required for precise regulation of cell- and tissue-specific gene expression programmes, which, in turn, is indispensable for proper development and function of the organism. Conversely, defects in gene expression processes have been linked to several human diseases including neurological and neuropsychiatric conditions such as myotonic dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, and possibly Alzheimer's disease. These devastating disorders are associated with considerable patient suffering and mortality as well as a serious burden for the national health system.Notably, cells employ quality control (QC) mechanisms that can minimise deleterious effects of erroneous gene expression by identifying and eliminating defective messenger molecules. An important but poorly understood branch of the cellular QC prevents export of incompletely processed gene transcripts containing intervening intron sequences from the nucleus to the cytoplasm thus preventing their translation into aberrant proteins. Transcripts retained by this mechanism in the nucleus are eventually eliminated. Previous studies by our group and others have suggested that, in addition to its error surveillance role, this nuclear retention and elimination (NRE) pathway may function in the context of developing nervous system (NS) as a regulatory mechanism enabling deterministic control of important neuronal genes. However, molecular mechanisms underlying NRE in human and animal cells in general and NS cells in particular are poorly understood.To this end, we propose to investigate mammalian NRE machinery using a combination of candidate and unbiased discovery approaches. We additionally propose to examine developmental changes in the NRE apparatus and their biological consequences in the NS context. To advance these lines of research, we will use a combination of established molecular, cellular and developmental biology techniques and will additionally develop innovative experimental approaches. We are convinced that the proposed work will shed light on molecular mechanisms ensuring accuracy of our gene expression programme and begin uncovering novel gene regulation mechanisms contributing to NS development and function. By elucidating these important aspects the proposed work should also improve our understanding of molecular causes leading to NS diseases and ultimately pave the way to new knowledge-based therapies and diagnostic tools.

我们基因的表达通过几个精心安排的步骤进行，包括初级转录物转录和加工成成熟的信使分子，信使从细胞核输出到细胞质，以及它们翻译成相应的蛋白质产物。这种复杂的过程是精确调节细胞和组织特异性基因表达程序所必需的，而这反过来又是生物体正常发育和功能所不可或缺的。相反，基因表达过程中的缺陷与几种人类疾病有关，包括神经和神经精神疾病，如强直性肌营养不良、脊髓性肌萎缩、肌萎缩性侧索硬化、额颞叶痴呆和可能的阿尔茨海默病。这些破坏性疾病与相当大的患者痛苦和死亡率以及国家卫生系统的严重负担有关。值得注意的是，细胞采用质量控制（QC）机制，可以通过识别和消除有缺陷的信使分子来最大限度地减少错误基因表达的有害影响。细胞QC的一个重要但知之甚少的分支阻止含有间插内含子序列的不完全加工的基因转录物从细胞核输出到细胞质，从而阻止它们翻译成异常蛋白质。通过这种机制保留在细胞核中的转录本最终被消除。我们小组和其他人以前的研究表明，除了其错误监视作用外，这种核保留和消除（NRE）途径可能在发育神经系统（NS）的背景下起作用，作为一种调节机制，能够确定性地控制重要的神经元基因。然而，NRE在人类和动物细胞中的分子机制，特别是NS cells知之甚少，为此，我们建议研究哺乳动物NRE机制，使用候选人和无偏见的发现方法相结合。此外，我们还建议研究NRE装置的发育变化及其在NS背景下的生物学后果。为了推进这些研究领域，我们将结合现有的分子、细胞和发育生物学技术，并开发创新的实验方法。我们相信，拟议的工作将阐明分子机制，确保我们的基因表达计划的准确性，并开始发现新的基因调控机制，有助于NS的发展和功能。通过阐明这些重要方面，拟议的工作也应该提高我们对导致NS疾病的分子原因的理解，并最终为新的基于知识的治疗和诊断工具铺平道路。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.

DOI：
10.1093/nar/gkx225
发表时间：
2017-06-20
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Collins KM;Kainov YA;Christodolou E;Ray D;Morris Q;Hughes T;Taylor IA;Makeyev EV;Ramos A
通讯作者：
Ramos A

A mechanism underlying position-specific regulation of alternative splicing.