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Identifying the RNA Splicing and Gene Expression Changes that cause Congenital Myotonic Dystrophy

识别导致先天性强直性肌营养不良的 RNA 剪接和基因表达变化

基本信息

批准号：
9912857
负责人：
Nicholas Elwood Johnson
金额：
$ 53.58万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-19 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912857
关键词：
Adult Age Alternative Splicing Behavioral Biological Biological Markers Biopsy Birth Breathing Cataract Cell model Child Childhood Clinical Cognition Congenital Myotonic Dystrophy Cross-Sectional Studies Data Development Disabled Children Disease Distal Dose Enrollment Event Fatigue Fine needle aspiration biopsy Future Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Hereditary Disease Impairment Individual Life Link Measures Molecular Motor Muscle Muscle Development Muscle function Muscle hypotonia Muscle relaxation phase Muscular Dystrophies Myotonia Myotonic Dystrophy Myotonic dystrophy type 1 Natural History Neuropsychology Outcome Measure Parents Participant Pathogenesis Pathogenicity Pathology Pattern Phase Phenotype Physical Function Population Problem behavior Proteins Published Comment RNA RNA Splicing Research Research Personnel Respiratory Insufficiency Risk Role Sampling Symptoms Testing Therapeutic Trials Transcript Variant Visit Work autistic biobank biomarker development clinical phenotype clinical predictors clinically relevant cohort design drug development early onset expectation experimental study feeding functional outcomes gastrointestinal symptom induced pluripotent stem cell molecular marker mortality new therapeutic target novel public health relevance research clinical testing specific biomarkers therapeutic development therapeutic target therapy development transmission process

项目摘要

Abstract Congenital myotonic dystrophy, the most severe form of myotonic dystrophy, causes weakness, breathing problems, and feeding problems at birth. During childhood, children often have intellectual impairment, fatigue, behavioral concerns and weakness. Importantly, many of the symptoms are distinct from those adults with myotonic dystrophy. In adults with myotonic dystrophy, a toxic RNA repeat expansion leads to global misregulation of RNA splicing. It is not clear if the same mechanism is involved in congenital myotonic dystrophy. Such information is critical since new treatments for myotonic dystrophy target this issue. This proposal is designed to evaluate the pathogenesis of congenital myotonic dystrophy. The investigators will evaluate changes in RNA splicing and gene expression in muscle samples and then validate these changes in a DM1 cell model by enrolling 100 children below the age of 15 with congenital myotonic dystrophy. Children will be evaluated with measures of physical function and cognition at the baseline visit and a fine needle aspirate of the muscle will be collected. Children with congenital myotonic dystrophy will return for a clinical evaluation at 12 months. These children will be compared to 30 histopathologically normal muscle biopsies. In Aim 1, we will initially evaluate changes in RNA splicing and correlate these with the clinical outcome measures to identify those specific transcripts that most directly correlate with symptoms. Key RNA splicing events will be evaluated as predictors of clinical function at the 12-month visit. In Aim 2, we will also evaluate secondary gene expression changes in a similar manner, which has not been done in myotonic dystrophy. Once key gene expression and RNA splicing signatures have been identified, Aim 3 will evaluate them in a DM1 cell model to assess the role of MBNL1 sequestration and other splicing regulators for a particular splice event. This is a key pathogenic mechanism in DM1. At the completion of this project, we will have identified key biomarkers and performed preliminary experiments to understand the role of these events in the mechanism of disease. By better understanding the pathogenesis of congenital myotonic dystrophy, we allow these children access to disease modifying therapies in myotonic dystrophy, as well as identify new therapeutic targets for drug development.

摘要先天性强直性肌营养不良，强直性肌营养不良的最严重形式，虚弱，呼吸问题，出生时的喂养问题。在童年时期，孩子们经常有智力障碍、疲劳、行为问题和虚弱。重要的是，许多这些症状与患有强直性肌营养不良的成年人不同。成人肌强直性营养不良，一种有毒的RNA重复扩增导致RNA剪接的整体失调。不先天性肌强直性营养不良是否涉及相同的机制尚不清楚。该等资料不这一点至关重要，因为强直性肌营养不良症的新治疗方法正是针对这一问题。该提案旨在探讨先天性强直性肌营养不良的发病机制。调查人员将评估肌肉样本中RNA剪接和基因表达的变化，然后验证这些通过招募100名15岁以下患有先天性心脏病的儿童，强直性肌营养不良将对儿童进行身体功能评估，将在基线访视时测量患者的认知，并收集肌肉的细针抽吸物。儿童患有先天性强直性肌营养不良的患者将在12个月时返回进行临床评估。这些将儿童与30例组织病理学正常的肌肉活检进行比较。在目标1中，我们将首先评估RNA剪接的变化，并将这些变化与临床结果测量，以确定那些最直接相关的特定转录本，症状关键RNA剪接事件将作为临床功能的预测因子进行评价， 12-月访问。在目标2中，我们还将评估类似的基因表达变化。这在强直性肌营养不良中还没有完成。一旦关键基因表达和RNA 剪接签名已经确定，目标3将在DM1细胞模型中评估它们，以评估 MBNL1螯合和其他剪接调节因子对特定剪接事件的作用。这是DM 1的一个重要致病机制。在这个项目完成后，我们将确定关键的生物标志物，并进行了初步实验，以了解这些事件的作用疾病的机制。通过更好地了解先天性肌强直的发病机制，营养不良，我们允许这些儿童获得疾病修饰治疗肌强直营养不良，以及确定药物开发的新治疗靶点。