Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

肌营养不良症的磁共振成像和生物标志物

基本信息

批准号：
8069808
负责人：
KRISTA H VANDENBORNE
金额：
$ 136.33万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-05 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069808
关键词：
14 year old Activities of Daily Living Address Adipose tissue Adrenal Cortex Hormones Affect Age Ankle Area Biological Markers Biopsy Cell Therapy Cells Cessation of life Characteristics Clinical Clinical Trials Communities Cross-Sectional Studies Deposition Dermal Development Disease Disease Progression Duchenne muscular dystrophy Dystrophin Effectiveness Evaluation Explosion Fatty acid glycerol esters Feedback Fibroblasts Flexor Florida Future Genomics Genotype Glucocorticoids Goals Health Sciences Imaging technology Infiltration Inflammation Intervention Intramuscular Isometric Exercise Knee Limb-Girdle Muscular Dystrophies Link Lipids Longitudinal Studies Lower Extremity Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Manuals Measurement Measures Medical Imaging Monitor Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscular Dystrophies Mutation Myoblasts Myopathy Neuromuscular Diseases Nonsense Codon Oligonucleotides Oregon Outcome Measure Pathogenesis Patients Pediatric Hospitals Pharmacotherapy Phenotype Philadelphia Physiology Preclinical Drug Evaluation Process Property Quality of life Randomized Controlled Trials Relaxation Research Design Resources Sampling Serum Severity of illness Site Skeletal Muscle Source Spectrum Analysis Staging Steroids Structural Protein Subgroup Techniques Technology Testing Therapeutic Effect Therapeutic Intervention Time Tissue Banking Tissue Banks Tissues Translations Universities Validation Walking Water boys design effective therapy gene therapy clinical trial improved information gathering mouse model muscle strength muscular structure outcome forecast preclinical study premature public health relevance quadriceps muscle repository restoration standard measure standard of care tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to validate the potential of noninvasive magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and to serve as a surrogate outcome measure for clinical trials in Duchenne muscular dystrophy (DMD). DMD is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis for patients with muscular dystrophy, therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function and quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. As such, this proposal targets the development and validation of magnetic resonance as a noninvasive biomarker of disease progression in muscular dystrophy. Using a multi-site research design this study will examine the intramuscular lipid content, muscle damage/inflammation and contractile area in the lower extremity muscles of 100 ambulatory boys with DMD and 50 healthy age matched boys using a combination of MRI and MRS technologies. In order to assess the sensitivity of each MR measure to disease progression, all boys with DMD will be re-evaluated in yearly or 6 month intervals. In addition, we will correlate changes in MR measures with standard measures of disease progression, such as loss in muscle strength and functional ability. Using MRI/MRS we will also examine the effect of initiating corticosteroid treatment on skeletal muscle characteristics and composition. Finally, we will deposit immortalized fibroblasts from carefully characterized DMD boys participating in this study in established tissue repositories. We anticipate that the MR techniques developed and validated in this proposal will be suitable for clinical trials in a wide range of muscular dystrophies and other neuromuscular diseases. In addition, MR characterization may serve as a powerful tool to further advance our understanding of the pathogenesis of muscular dystrophy and help guide the design of future trials. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a way to observe whether or not new therapies are effective in correcting the disease process in muscles of boys with Duchenne muscular dystrophy (DMD) without the need to take muscle biopsies. We have evidence in mouse models of both DMD and limb girdle muscular dystrophy that magnetic resonance imaging can be used to track disease progression and monitor the effectiveness of therapeutic interventions. We will extend our past mouse studies to boys with DMD.

描述（由申请人提供）：本提案的总体目标是验证无创磁共振成像 (MRI) 和光谱学 (MRS) 监测疾病进展的潜力，并作为杜氏肌营养不良症临床试验的替代结果指标（DMD）。 DMD 是最具破坏性的遗传性神经肌肉疾病之一，其特征是肌营养不良蛋白的缺失，导致进行性肌肉无力、行走能力丧失和过早死亡。尽管肌营养不良症患者的预后较差，但仍缺乏治疗干预措施，临床试验的结果测量仅限于肌肉功能和生活质量、肌肉分解的血清生物标志物和侵入性肌肉活检。需要额外的非侵入性且对肌肉结构和成分变化敏感的定量结果测量，以促进有前途的新干预措施从临床前研究到临床试验的快速转化。因此，该提案的目标是开发和验证磁共振作为肌营养不良症疾病进展的非侵入性生物标志物。本研究采用多中心研究设计，将结合 MRI 和 MRS 技术，检查 100 名患有 DMD 的流动男孩和 50 名年龄匹配的健康男孩的下肢肌肉的肌内脂质含量、肌肉损伤/炎症和收缩区域。为了评估每个 MR 测量对疾病进展的敏感性，所有患有 DMD 的男孩将每年或每 6 个月进行一次重新评估。此外，我们还将 MR 测量值的变化与疾病进展的标准测量值（例如肌肉力量和功能能力的丧失）相关联。我们还将使用 MRI/MRS 检查开始皮质类固醇治疗对骨骼肌特征和组成的影响。最后，我们将把参与这项研究的 DMD 男孩的永生化成纤维细胞存放在已建立的组织储存库中。我们预计本提案中开发和验证的 MR 技术将适用于各种肌营养不良症和其他神经肌肉疾病的临床试验。此外，MR 表征可以作为一个强大的工具，进一步增进我们对肌营养不良症发病机制的理解，并帮助指导未来试验的设计。公共健康相关性：该项目的目标是开发一种方法来观察新疗法是否能有效纠正患有杜氏肌营养不良症 (DMD) 的男孩的肌肉疾病过程，而无需进行肌肉活检。我们在 DMD 和肢带型肌营养不良症小鼠模型中获得的证据表明，磁共振成像可用于跟踪疾病进展并监测治疗干预措施的有效性。我们将把过去的小鼠研究扩展到患有 DMD 的男孩。