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.

抽象的先天性强直性肌营养不良是强直性肌营养不良最严重的形式，其原因出生时虚弱、呼吸问题和喂养问题。在童年时期，孩子们常常有智力障碍、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。患有肌强直的成人营养不良，有毒的RNA重复扩增导致RNA剪接的整体失调。它不是明确先天性强直性肌营养不良是否涉及相同的机制。此类信息是至关重要，因为强直性肌营养不良的新疗法针对的是这个问题。本提案设计评估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 岁以下患有先天性疾病的儿童来改变 DM1 细胞模型强直性肌营养不良。儿童将接受身体机能测量和将收集基线访视时的认知和肌肉的细针抽吸物。孩子们先天性强直性肌营养不良患者将在 12 个月时返回接受临床评估。这些儿童将与 30 个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，以确定与最直接相关的那些特定转录本症状。关键的 RNA 剪接事件将作为临床功能的预测因子进行评估为期12个月的访问。在目标 2 中，我们还将以类似的方式评估次要基因表达变化方式，这在强直性肌营养不良中尚未完成。一旦关键基因表达和RNA 剪接特征已被识别，Aim 3将在DM1细胞模型中对其进行评估以评估 MBNL1 隔离和其他剪接调节因子在特定剪接事件中的作用。这是 DM1 的关键致病机制。在该项目完成时，我们将确定关键生物标志物并进行初步实验以了解这些事件的作用在发病机制上。通过更好地了解先天性肌强直的发病机制营养不良，我们允许这些孩子接受肌强直的疾病修饰疗法营养不良，以及确定药物开发的新治疗靶点。