Magnetic Resonance Imaging and Biomarkers for Muscular Dystropy

肌营养不良症的磁共振成像和生物标志物

• 批准号: 8958272
• 负责人: KRISTA H VANDENBORNE
• 金额: $ 147.27万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-05 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958272
• 关键词: 7 year old; Academia; Address; Adrenal Cortex Hormones; Advocacy; Age; Age Distribution; Biological; Biological Markers; Blood; Clinical Trials; Clinical Trials Design; Communities; Data; Data Collection; Deposition; Development; Disease; Disease Progression; Duchenne muscular dystrophy; Educational workshop; Enrollment; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Forearm; Funding; Future; Genetic; Goals; Grant; Incidence; Industry; Inflammation; Knowledge; Left; Leg; Life; Link; Lower Extremity; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Monitor; Multicenter Studies; Muscle; Muscle Weakness; Muscular Dystrophies; Natural History; Neuromuscular Diseases; Outcome Measure; Pathology; Patients; Performance; Population; Predictive Value; Recruitment Activity; Research Infrastructure; Resources; Sampling; Shoulder; Site; Spectrum Analysis; Staging; Statistical Models; Stress; Testing; Time; Tissues; Upper Extremity; Upper arm; Urine; Validation; Walking; arm; biceps brachii muscle; boys; cohort; deltoid muscle; design; emerging adult; experience; imaging biomarker; improved; inclusion criteria; interest; loss of function; meetings; multidisciplinary; muscular structure; public health relevance; spectroscopic imaging; therapeutic development; therapeutic target; therapy development

 DESCRIPTION (provided by applicant): Over the last decade tremendous progress has been made in identifying therapeutic targets for Duchenne muscular dystrophy (DMD), a devastating progressive neuromuscular disease. However the design of clinical trials has been challenging, with sparse natural history data, a limited patient pool to recruit from, and few sensitive noninvasive outcome measures. Recent setbacks in several clinical trials have underscored the crucial need for transitional outcome measures that are sensitive across various stages of disease progression, including in non-ambulatory boys, and can reliably be implemented at multiple sites. In the initial funding cycle of this grant, we successfully implemented the first multicenter MR study in DMD and demonstrated that lower extremity quantitative MR measures (e.g. MRS fat fraction and MRI/MRS T2) are sensitive to disease progression in ambulatory boys, responsive to corticosteroid treatment, and reliable across multiple sites. In Aim 1 of this renewal application, we propose to extend the natural history MR biomarker study (iDMD) in the lower extremity muscles. Given the age distribution of the iDMD subject cohort (n=136; ages 7-18 years) we have an unprecedented opportunity to examine the sensitivity of quantitative MR measures (including 8-point Dixon and UTE) at different stages of disease progression, assess their value in predicting loss of ambulation, and obtain extremely valuable long term natural history data. In Aim 2, we will develop and validate upper extremity MR biomarkers and outcome measures in the same subject cohort. Specifically, we will perform a detailed MRI/MRS characterization of the forearm, upper arm and shoulder girdle. No prior MR imaging studies in DMD have been performed on upper extremity muscles that are essential for function, such as the biceps and deltoid, leaving a considerable gap in knowledge. MR measures in boys with DMD will be repeated at yearly intervals. In addition, we will correlate changes in MRI/MRS measures with loss in upper extremity function and strength. Finally, in Aim 3 we will build on our current infrastructure to establish a National Tissue and Data Resource, linking biological samples (fibroblasts, blood/urine) with genetic, detailed MRI/MRS, strength, functional, and demographic data collected in iDMD and making them available to the larger DMD community. This project addresses several critical barriers in therapeutic development and has the potential to significantly improve future clinical trials in DMD, as well as other neuromuscular diseases.

 描述（由适用提供）：在过去的十年中，在识别Duchenne肌肉营养不良症（DMD）的治疗靶点方面取得了巨大进展，这是一种毁灭性的渐进性神经肌肉疾病。然而，临床试验的设计受到挑战，具有稀疏的自然病史数据，有限的患者库可从中招募，并且敏感的无创结局指标。在几项临床试验中，最近的挫折强调了对疾病进展的各个阶段（包括非肢体男孩）敏感的过渡结果指标的关键需求，并且可以在多个地点可靠地实施。在该赠款的最初基础周期中，我们成功地实施了DMD中的第一个多中心MR研究，并证明下肢定量MR测量值（例如，脂肪级分和MRI/MRI/MRI/MRS T2）对卧床男孩的疾病进展敏感，对皮质类固醇治疗的响应响应，并且在多个地点之间可靠。在此更新应用的目标1中，我们建议将自然史MR生物标志物研究（IDMD）扩展到下肢肌肉中。鉴于IDMD受试者队列的年龄分布（n = 136； 7-18岁），我们有前所未有的机会，可以检查疾病进展的定量MR测量值（包括8点Dixon和UTE）的敏感性，在预测行进性损失的价值时，并获得了非常有价值的长期自然历史历史数据。在AIM 2中，我们将在同一受试者队列中开发和验证上肢MR生物标志物和结果指标。具体来说，我们将对前臂，上臂和肩膀女孩进行详细的MRI/MRS表征。尚未对DMD的先前MR成像研究对在功能所必需的上肢肌肉（例如二头肌和三角肌）上进行，在知识中留下了很大的差距。 DMD男孩的MR测量将每年重复。此外，我们将将MRI/MRS测量的变化与上肢功能和强度损失相关联。最后，在目标3中，我们将建立我们当前的基础设施，以建立国家组织和数据资源，将生物学样本（成纤维细胞，血液/尿液）与遗传，详细的MRI/MRI/MRS，强度，功能和人口统计数据联系起来，并在IDMD中收集的人口统计数据以及使它们可用于较大的DMD社区。该项目解决了热发育中的几个关键障碍，并有可能显着改善DMD以及其他神经肌肉疾病的未来临床试验。