Health Endpoints and Longitudinal Progression in Congenital Myotonic Dystrophy (HELP-CDM)

先天性强直性肌营养不良的健康终点和纵向进展 (HELP-CDM)

基本信息

批准号：
8999032
负责人：
Nicholas Elwood Johnson
金额：
$ 19.46万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8999032
关键词：
Address Adult Affect Age Antisense Oligonucleotides Binding Biological Biological Markers Biological Models Biology Biopsy Birth Blood Blood Cells Cardiac Cell Line Child Childhood Clinical Cognition Cohort Studies Congenital Myotonic Dystrophy Congenital clubfoot Data Development Disabled Children Disease Disease Progression Enrollment Functional disorder Future Genes Genetic Translation Global Change Goals Health Image Impairment Inborn Genetic Diseases Intellectual functioning disability Investigation Laboratories Lead Leukocytes Life Longitudinal Studies Measures Medicine Messenger RNA Morbidity - disease rate Motor Muscle Muscle function Muscle hypotonia Myotonic Dystrophy Other Multiple Areas Outcome Parents Pathogenesis Patients Pattern Peripheral Blood Mononuclear Cell Process Proteins Protocols documentation Quality of life RNA RNA Splicing RNA-Binding Proteins Research Research Personnel Resources Respiratory Failure Respiratory Insufficiency Respiratory physiology Risk Speech Structure Symptoms Techniques Therapeutic Trials Training Transcript Translating Translational Research Translations Trinucleotide Repeat Expansion Variant age related base blood-based biomarker clinical phenotype clinically relevant cohort design experience feeding fundamental research gastrointestinal symptom infancy lymphoblastoid cell line mortality neuromuscular neuropsychiatry novel novel therapeutics offspring patient population potential biomarker research study therapy development transcriptome sequencing treatment trial

项目摘要

DESCRIPTION (provided by applicant): Congenital myotonic dystrophy is due to the rapid enlargement of the disease-causing CTG trinucleotide repeat expansion between a parent with myotonic dystrophy and their offspring resulting in symptoms at birth. Congenital myotonic dystrophy causes significant morbidity and mortality due to early life respiratory failure, intellectual disability, weakness, and a number of systemic complications. Before RNA is translated into proteins, the RNA is cut, or spliced, so that the correct form of the protein is made based on age and other factors. In adults with myotonic dystrophy, the CTG repeat impairs this process resulting in abnormal splicing of many important RNA transcripts which in turn leads to the diverse disease manifestations. It is not known whether the same disease mechanism occurs in congenital myotonic dystrophy. As developing therapies for myotonic dystrophy target this mechanism, it is imperative to understand if this process also occurs in congenital myotonic dystrophy. This proposal seeks to better understand how the CTG repeat expansion causes disease in children with congenital myotonic dystrophy. The results will lead to a better understanding of disease progression and prepare for approaching therapeutic trials. We hypothesize that RNA splicing changes are responsible for disease progression in childhood. A secondary aim of the study is to identify blood-based biomarkers such as RNA splice variation or other observed protein changes, which could facilitate future therapeutic trials. This study utilizes an existing longitudinal disease progression cohort with congenital myotonic dystrophy. In this study, children with congenital myotonic dystrophy have measures of neuropsychiatric function, muscle function, cardiac conduction, respiratory function, speech, and quality of life. The current proposal seeks to identify disease-causing RNA splicing changes. In addition, this study will examine global changes in translation that occur as the result of sequestration of RNA-binding proteins. Finally, this study will identify how well the changes in RNA splicing and translation correlate with the clinical endpoints in the disease progression. The results will provide a complete clinical and biological model for congenital myotonic dystrophy disease progression. This critical information will permit development of appropriate clinical and biological endpoints for therapeutic trials. In addition, this project wil provide the investigator techniques in fundamental research in RNA biology.

描述（由申请人提供）：先天性强直性肌营养不良是由于强直性肌营养不良的父母及其后代之间引起疾病的 CTG 三核苷酸重复扩增导致出生时出现症状。先天性强直性肌营养不良导致显着的发病率和死亡率。生命早期呼吸衰竭、智力障碍、虚弱和一些全身并发症在 RNA 被翻译成蛋白质之前，RNA 被切割或剪接，以便形成正确的形式。该蛋白质是根据年龄和其他因素产生的，在患有强直性肌营养不良的成年人中，CTG 重复会损害这一过程，导致许多重要 RNA 转录物的异常剪接，从而导致不同的疾病表现。目前尚不清楚是否存在相同的疾病。强直性肌营养不良症的机制发生在先天性强直性肌营养不良症中。 CTG 重复扩增会导致患有先天性强直性营养不良的儿童患病。该结果将有助于更好地了解疾病进展，并为即将进行的治疗试验做好准备，我们认为 RNA 剪接变化是导致儿童疾病进展的原因。目的是识别基于血液的生物标志物，例如 RNA 剪接变异或其他观察到的蛋白质变化，这可以促进未来的治疗试验。强直性肌营养不良症有神经精神功能、肌肉功能、心脏传导、呼吸功能、言语和生活质量的指标，目前的提议旨在识别引起疾病的 RNA 剪接变化。此外，这项研究将检查翻译中发生的整体变化。最后，这项研究将确定 RNA 剪接和翻译的变化与疾病进展的临床终点的相关性如何，结果将为先天性癌症提供完整的临床和生物学模型。此外，该项目还将为研究人员提供 RNA 生物学基础研究的技术。