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 强直性肌营养不良症(DM)是最常见的肌营养不良症，会导致所有肌肉的症状 类型，表现为骨骼肌萎缩、心律失常和胃肠功能障碍。一个多系统的 除了糖尿病，糖尿病还通常影响中枢神经、内分泌和生殖系统。 糖尿病是由扩大的CTG或CCTG重复序列引起的，这些重复序列被转录成RNA，隔离了 如(MBNL)RNA结合蛋白，并滴定它们远离其正常的mRNA靶标。Cug重复表达式 也导致CUGBP/ELAV样因子(CELF)的过度磷酸化，导致CELF蛋白升高。 MBNLS和CELFS的失调会导致数百种转录组的变化，包括许多 另一种拼接。到目前为止，糖尿病转录组的全谱变化仍然没有特征化，而且它是 尚不清楚MBNL和CELF扰动是否能完全解释这些变化。此外，分子 目前只发现了几种糖尿病症状的原因。 MBNL蛋白介导的另一个细胞过程是RNA定位。RNA的亚细胞定位 对许多细胞和生理过程都很重要，包括细胞运动、胚胎构型和 突触功能。然而，我们对RNA定位的理解仍然局限于TRAN-R的一小部分。 脚本，我们缺乏RNA本地化如何实现的分子部件列表。确认这些球员的身份将 揭示了在糖尿病和其他疾病中，RNA错误定位在多大程度上促进了病理。因此，我们 将系统地描述DM的转录组变化，并评估MBNL和CELF在多大程度上通过 扰动可以解释DM转录本的这些变化(目标1)。我们将定义用于RNA本地化的部件列表， 包括顺式和反式元件，并阐明这些角色如何控制RNA的亚细胞分布(目标2)。 我们将研究基因表达的所有步骤，包括剪接、RNA定位和翻译的变化可能 与DM表型有关，并开发治疗方法来纠正这些变化(目标3)。 总之，这项工作的完成将进一步加深我们对DM这一范式中的分子变化的理解 对于RNA毒性疾病，为更好地理解RNA定位奠定基础，并帮助将这些 分子事件对生理学的影响。 公共卫生相关性：糖尿病是最常见的肌肉营养不良形式，是一种 由核糖核酸毒性引起的一类疾病。了解糖尿病的分子变化并将其与表型联系起来 将帮助我们了解疾病表型是如何产生的，以及如何治疗它们。