IMAGING OF FAILED REGENERATION IN MUSCLES OF MUSCULAR DYSTROPHY PATIENTS

肌营养不良症患者肌肉再生失败的成像

• 批准号: 9119605
• 负责人: GLENN WALTER
• 金额: $ 28.74万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-25 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9119605
• 关键词: 15 year old; Abdominal Muscles; Address; Adult; Affect; Age; Alleles; Binding Proteins; Biological; Biological Markers; Biological Preservation; Breathing; Cardiac; Cardiomyopathies; Cessation of life; Clinical Trials; Coupled; Data; Dependence; Disease; Disease Progression; Duchenne muscular dystrophy; Dystrophin; Environment; Fatty acid glycerol esters; Fibrosis; Functional disorder; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Heart; Heart Diseases; Heterogeneity; High Prevalence; Homozygote; Image; Individual; Inflammation; Inflammatory; Injury; Intercostal Muscles; Intramuscular; Leg; Limb structure; Longitudinal Studies; Lower Extremity; Lung; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Mendelian disorder; Monitor; Muscle; Muscle Fibers; Muscle Weakness; Muscular Atrophy; Muscular Dystrophies; Myocardial; Myocardium; Natural History; Natural regeneration; Neuromuscular Diseases; Outcome Measure; Pathology; Patients; Peripheral; Process; Promoter Regions; Prospective Studies; Recruitment Activity; Reporting; Respiratory Diaphragm; Respiratory Insufficiency; Respiratory Muscles; Respiratory Tract Infections; Respiratory physiology; Retrospective Studies; Sampling; Severity of illness; Signal Transduction; Skeletal Muscle; Stratification; Testing; Thigh structure; Time; Transforming Growth Factor beta; Transforming Growth Factors; United States National Institutes of Health; Variant; Ventilator; base; boys; cohort; disease-causing mutation; experience; imaging biomarker; improved; innovation; muscular system; new therapeutic target; novel; osteopontin; patient population; premature; pulmonary function; pulmonary function decline; therapeutic development

Project Summary Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease caused by mutations in dystrophin and characterized by progressive muscle weakness, early loss of ambulation, cardiomyopathy and respiratory insufficiency. Clinical trials in DMD have been hampered by limited natural history data and a lack of sensitive noninvasive outcome measures. In addition, this single-gene disease displays considerable variability in disease severity. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. In this renewal application, we will examine the impact of polymorphisms reported to affect disease progression, including SPP1 and LTBP4, relative to magnetic resonance imaging (MRI) biomarkers. LTBP4 encodes the latent transforming growth factor (TGF) β binding protein (LTBP4), that is highly expressed in both cardiac and skeletal muscle, and regulates the release of active TGFβ. DMD patients homozygous for the IAAM LTBP4 haplotype have been reported to demonstrate preserved ambulatory function and reduced TGFβ signaling compared to patients heterozygous or homozygous for the VTTT haplotype. Genotype at polymorphism rs28357094 in the promoter region of the SPP1 gene, encoding osteopontin, has been shown to influence muscle size and eccentric injury in healthy adults, as well as disease severity in DMD. To examine the association between these genetic polymorphisms and MRI biomarkers we will take advantage of the natural history lower extremity Magnetic Resonance images and biological samples acquired in a large DMD cohort (ImagingDMD). In addition, we will develop novel MRI strategies to monitor disease progression in the heart and respiratory muscles. This will be the first imaging study to monitor muscle pathology in the intercostal and abdominal muscle in boys with DMD. We hypothesize that DMD patients with the protective LTBP4 haplotype will demonstrate slower rates of cardiac disease progression and less severe pathophysiology in the respiratory muscles. The results of this study may ultimately be important for the stratification of homogenous patients for clinical trials, help identify new therapeutic targets, and provide new biomarkers for clinical trials targeting respiratory function.

项目总结