Structural and Functional CMS Changes in Children with Myotonic Dystrophy

强直性肌营养不良儿童的结构和功能 CMS 变化

基本信息

批准号：
7805432
负责人：
JOHN W DAY
金额：
$ 20.49万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7805432
关键词：
3&apos Untranslated Regions Adult Affect Age Animals Autopsy Brain region Cell Nucleus Cell physiology Cells Central Nervous System Diseases Cerebellar cortex structure Cerebrum Child Chromosomes, Human, Pair 19 Chromosomes, Human, Pair 3 Clinical Code Collaborations Complement Cross-Sectional Studies Defect Degenerative Disorder Development Diffuse Diffusion Magnetic Resonance Imaging Disease Elements Etiology Evaluation Family Foundations Functional disorder Future Genes Growth Human Image Individual Introns Investigation Length Letters Longitudinal Studies Magnetic Resonance Imaging Measures Mental Retardation Methods Methylation Modeling Molecular Molecular Genetics Molecular Target Morbidity - disease rate Mus Muscular Dystrophies Mutation Myotonic Dystrophy Natural History Neurocognitive Neurodegenerative Disorders Pathogenesis Pathology Patients Pattern Phenocopy Phosphotransferases Physiological Positioning Attribute Principal Investigator Proteins Questionnaires RNA RNA Splicing Research Role Secure Severities Site Structure Support Groups Therapy Clinical Trials Time Toxic effect Transgenic Animals Transgenic Mice base cerebral atrophy clinically significant early onset executive function experience frontal lobe gray matter improved insight interest longitudinal human study mouse model neuropathology neurophysiology neuropsychological optical imaging patient population programs therapeutic target trend white matter

项目摘要

Structural and Functional CNS Changes in Children with Myotonic Dystrophy Type 1 Myotonic Dystrophy (DM), the most prevalent form of muscular dystrophy, is a multisystemic disorder caused by mutations on chromosome 19 (DM1) or chromosome 3 (DM2). The pathophysiological effects of the DM1 mutation are controversial because it is an untranslated CTG expansion, and thus causes this progressive and ultimately fatal disease without altering the coding portion of any gene. The discovery that DM2 is caused by a similarly untranslated CCTG expansion, along with other discoveries about DM1 pathogenesis, have helped define a new disease mechanism in which RNA containing CUG or CCUG expansions affects cell function, at least partly by altering splicing of many genes. Our comparisons of DM1 and DM2 show that features common to both diseases result from these RNA effects, though controversy remains as to the molecular pathophysiology of features that differ in the two forms of DM. Much of DM morbidity results from CNS deficits. Because some CNS effects differ in DM1 and DM2, the role of the toxic RNA mechanism in CNS pathophysiology is controversial. We have defined CNS MRI and neuropsychological changes in DM children and adults, including: 1) loss of frontal lobe volume; 2) frontal white matter disorganization measured by diffusion tensor imaging; 3) altered executive function. The CNS abnormalities common to DM1 and DM2 almost certainly result from the toxic-RNA mechanism. We now propose to investigate children with early-onset DM1 to better define the structural and functional CNS abnormalities. Our specific aims are to: 1) determine whether early-onset DM1 causes structural CNS deficits in children that are similar to adult-onset DM1 and DM2; 2) determine whether children with DM1 have neuropsychological deficits that correspond to the structural abnormalities; 3) to determine the molecular features of early-onset DM1 by establishing whether repeat length or methylation status alter the likelihood of CNS involvement; 4) to develop a clinically useful measure of CNS involvement for future DM natural history and therapeutic trials. The proposed studies will improve our understanding of CNS involvement in patients with DM, and will inform the transgenic animal and molecular studies being performed in Projects 1 and 2 and in the Core of this Program. Together with Projects 1 and 2, this overall Program will elucidate clinical, cellular and molecular elements of CNS disease in DM, and help identify and evaluate therapeutic targets.

1型肌发育症儿童的结构和功能性中枢神经系统变化肌营养不良症（DM）是最普遍的肌肉营养不良的形式，是一种多系统疾病是由19号染色体（DM1）或3染色体（DM2）的突变引起的。的病理生理影响 DM1突变是有争议的，因为它是未翻译的CTG扩展，因此导致了这一点进行性疾病的进行性疾病，而没有改变任何基因的编码部分。发现 DM2是由类似未翻译的CCTG扩展以及其他关于DM1的发现引起的发病机理有助于定义了一种新的疾病机制，其中含有CUG或CCUG的RNA 扩展会影响细胞功能，至少部分通过改变许多基因的剪接。我们对DM1的比较 DM2表明，两种RNA效应引起的两种疾病的特征，尽管有争议保留在两种形式的DM形式的特征的分子病理生理学上。 DM发病率的大部分来自中枢神经系统缺陷。由于某些CNS效应在DM1和DM2中有所不同，因此有毒RNA机制在CNS病理生理学中的作用是有争议的。我们定义了CNS MRI和 DM儿童和成人的神经心理学变化，包括：1）额叶体积的损失； 2）正面通过扩散张量成像测量的白质混乱； 3）更改执行功能。中枢神经系统 DM1和DM2常见的异常几乎肯定是由于毒性RNA机制引起的。现在，我们建议调查患有早发DM1的儿童，以更好地定义结构和功能性中枢神经系统异常。我们的具体目的是：1）确定早期发作的DM1是否原因与成人发作DM1和DM2相似的儿童的结构中枢神经系统缺陷； 2）确定是否 DM1儿童的神经心理学缺陷与结构异常相对应； 3）到通过确定重复长度还是甲基化来确定早发DM1的分子特征地位改变了中枢神经系统参与的可能性； 4）制定CNS参与的临床有用度量对于未来的DM自然史和治疗试验。拟议的研究将改善我们的理解 CNS参与DM患者，并将告知转基因动物和分子研究在项目1和2和该程序的核心中执行。与项目1和2一起，这个总体程序将阐明DM中CNS疾病的临床，细胞和分子元素，并有助于识别和评估治疗靶标。