Post-transcriptional regulation of gene expression in neuromuscular disease

神经肌肉疾病基因表达的转录后调控

• 批准号: 8608404
• 负责人: Eric T Wang
• 金额: $ 38.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-27 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608404
• 关键词: Accounting; Actins; Address; Affect; Alternative Splicing; Animal Model; Anterior; Arrhythmia; Biochemical; Biological Assay; Biological Models; Cell Culture Techniques; Cell physiology; Cells; Communities; Disease; Drosophila genus; Elements; Embryo; Endocrine system; Event; FMRP; Fatigue; Fibroblasts; Fragile X Syndrome; Functional disorder; Gene Expression; Gene Expression Profile; Histocompatibility Testing; Individual; Inherited; Knowledge; Length; Link; Long-Term Potentiation; Mediating; Messenger RNA; Molecular; Mus; Muscle; Muscular Dystrophies; Myotonic Dystrophy; Neuraxis; Neuromuscular Diseases; Neurons; Pathology; Patients; Pattern; Phenotype; Phosphorylation; Physiological; Physiological Processes; Physiology; Post-Transcriptional Regulation; Process; Protein Secretion; Proteins; RNA; RNA Splicing; RNA-Binding Proteins; Reproductive system; Resolution; Resources; Role; Serum Proteins; Sleep disturbances; Spliced Genes; Symptoms; Synapses; Systemic disease; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Transcript; Translations; Work; base; biological systems; cell motility; cell type; clinically significant; experience; gastrointestinal; genome-wide; human disease; innovation; neuropsychological; novel; patient population; public health relevance; research study; single molecule; skeletal muscle wasting; synaptic function; transcriptome sequencing

Project Summary Myotonic dystrophy (DM) is the most common form of muscular dystrophy, and leads to symptoms in all muscle types, in the form of skeletal muscle wasting, cardiac arrhythmias, and gastrointestinal dysfunction. A multi-systemic disease, DM also commonly affects the central nervous, endocrine, and reproductive systems. DM is caused by expanded CTG or CCTG repeats, which are transcribed into RNA, sequestering the Muscleblind- like (MBNL) RNA binding proteins and titrating them away from their normal mRNA targets. CUG repeat expression also leads to hyper-phosphorylation of the CUGBP/ ELAV-like factors (CELFs), resulting in CELF protein elevation. Dysregulation of MBNLs and CELFs causes hundreds of changes to the transcriptome, including many changes in alternative splicing. To date, the full spectrum of transcriptome changes in DM remains uncharacterized, and it is unknown whether MBNL and CELF perturbation can fully account for those changes. Furthermore, the molecular causes of only a few DM symptoms have been discovered. Another cellular process mediated by the MBNL proteins is RNA localization. Subcellular localization of RNA is important for numerous cellular and physiological processes, including cell motility, embryonic patterning, and synaptic function. However, our understanding of RNA localization remains restricted to a small subset of tran- scripts, and we lack a molecular parts list for how RNA localization is achieved. Identification of these players will reveal the extent to which RNA mis-localization contributes to pathology in DM and other diseases. Therefore, we will systematically characterize transcriptome changes in DM and assess the extent to which MBNL and CELF per- turbation can explain these changes in DM transcriptomes (Aim 1). We will define a parts list for RNA localization, including cis- and trans- elements, and elucidate how these players control subcellular distribution of RNAs (Aim 2). We will study how changes in all steps of gene expression, including splicing, RNA localization, and translation, may be linked to DM phenotypes, and develop therapeutic approaches to correct these changes (Aim 3). Together, completion of this work will further our understanding of the molecular changes in DM, a paradigm for diseases of RNA toxicity, lay the groundwork for better understanding RNA localization, and help connect these molecular events to physiology. PUBLIC HEALTH RELEVANCE: DM is the most common form of muscular dystrophy, and is a paradigm for a class of diseases caused by RNA toxicity. Understanding molecular changes in DM and linking them to phenotypes will help us understand how disease phenotypes arise and how they can be treated.

项目摘要 肌营养不良症（DM）是肌肉营养不良的最常见形式，并导致所有肌肉的症状 骨骼肌浪费，心律不齐和胃肠道功能障碍的形式。多系统的 疾病，DM通常还会影响中枢神经，内分泌和生殖系统。 DM是由CTG或CCTG重复量扩展引起的，这些重复序列被转录为RNA，隔离了肌肉闪光 像（MBNL）RNA结合蛋白，并将其滴落在其正常的mRNA靶标中。 CUG重复表达 还导致CUGBP/ ELAV样因子（CELF）过度磷酸化，导致CELF蛋白升高。 MBNL和CELF的失调会导致转录组的数百个变化，包括许多变化 替代剪接。迄今 未知MBNL和CELF扰动是否可以完全解释这些变化。此外，分子 仅发现了几个DM症状的原因。 MBNL蛋白介导的另一个细胞过程是RNA定位。 RNA的亚细胞定位 对于许多细胞和生理过程，包括细胞运动，胚胎图案和 突触功能。但是，我们对RNA定位的理解仍然仅限于一小部分tran- 脚本，我们缺乏有关如何实现RNA定位的分子零件列表。这些球员的识别将 揭示了RNA错误定位对DM和其他疾病的病理有助于的程度。因此，我们 将系统地表征DM的转录组变化，并评估MBNL和CELF的程度 turgation可以解释DM转录组中的这些变化（AIM 1）。我们将定义RNA本地化的零件列表， 包括顺式和转移，并阐明这些参与者如何控制RNA的亚细胞分布（AIM 2）。 我们将研究基因表达的所有步骤的变化，包括剪接，RNA定位和翻译，可能 与DM表型联系起来，并开发出治疗方法来纠正这些变化（AIM 3）。 共同完成这项工作将进一步了解DM的分子变化，范式 对于RNA毒性疾病，为更好地理解RNA定位奠定了基础，并有助于连接它们 生理学的分子事件。 公共卫生相关性：DM是肌肉营养不良的最常见形式，是 由RNA毒性引起的疾病类别。了解DM的分子变化并将其链接到表型 将帮助我们了解疾病表型的出现以及如何治疗。