Role of FN14 in RNA Toxicity

FN14 在 RNA 毒性中的作用

基本信息

批准号：
8331374
负责人：
Mani Subramaniam Mahadevan
金额：
$ 34.65万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8331374
关键词：
3&apos Untranslated Regions Address Adult Affect Apoptosis Inhibitor Atrophic Breeding Cardiac Cells Child Collaborations Data Degenerative Disorder Disease Duchenne muscular dystrophy Electrocardiogram Evaluation Gene Expression Genes Genetic Genetic Transcription Goals Grant Hereditary Disease Histologic Histopathology Knockout Mice Ligands Mediator of activation protein Messenger RNA Methods Modeling Molecular Mus Muscle Muscle Weakness Muscle function Muscular Dystrophies Mutation Myocardium Myopathy Myotonic Dystrophy Nuclear Pathologic Pathology Pathway interactions Patients Phase I Clinical Trials Play Prevalence Process Production RNA Reverse Transcriptase Polymerase Chain Reaction Role Running Sampling Skeletal Muscle Symptoms System Therapeutic Intervention Therapy Clinical Trials Toxic effect Treadmill Tests Tumor Necrosis Factor-alpha cohort design effective therapy efficacy testing genetic analysis grasp mouse model muscle degeneration mutant myotonic dystrophy protein kinase novel receptor research study therapeutic development therapeutic target wasting

项目摘要

DESCRIPTION (provided by applicant): Myotonic dystrophy (DM1), the most common form of muscular dystrophy in adults and children, is a multi- systemic, autosomal dominant genetic disorder caused by a mutation that leads to the production of a mutant RNA that is toxic to cells. Currently there are no therapies for DM1. Muscle weakness and wasting are major debilitating factors in DM1 and yet very little is known about the molecular mediators or muscle pathology in DM1. We have developed a mouse model of RNA toxicity in which we have demonstrated reversal of muscle pathology by silencing the toxic RNA. We have used this model to identify new molecules, mechanisms and pathways involved in RNA toxicity in DM1. This particular grant is designed to use genetic analysis and therapeutic trials in our mouse model to address the role of one of the novel molecules that we have identified in order to assess its potential as a viable therapeutic target. This novel finding opens new opportunities for: 1) understanding muscle degeneration, and perhaps cardiac pathology in DM1 and 2) developing new therapies to treat muscular dystrophy in DM1.

描述（由申请人提供）：强直性肌营养不良 (DM1) 是成人和儿童肌营养不良最常见的形式，是一种多系统、常染色体显性遗传性疾病，由突变引起，该突变导致产生突变 RNA，该突变 RNA对细胞有毒。目前尚无针对 DM1 的治疗方法。肌肉无力和肌肉萎缩是 DM1 的主要衰弱因素，但人们对 DM1 的分子介质或肌肉病理学知之甚少。我们开发了一种 RNA 毒性小鼠模型，在该模型中，我们证明了通过沉默有毒 RNA 可以逆转肌肉病理学。我们使用该模型来识别与 DM1 中 RNA 毒性有关的新分子、机制和途径。这笔特别资助的目的是在我们的小鼠模型中使用遗传分析和治疗试验来解决我们已经确定的一种新分子的作用，以评估其作为可行治疗靶点的潜力。这一新发现为以下方面开辟了新的机会：1) 了解 DM1 中的肌肉变性，或许还有心脏病理学；2) 开发新疗法来治疗 DM1 中的肌营养不良症。