The Relationship between Genomic Variants and MRI/MRS Markers in DMD

DMD 基因组变异与 MRI/MRS 标记之间的关系

• 批准号: 8653370
• 负责人: GLENN WALTER
• 金额: $ 34.47万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653370
• 关键词: Affect; Age; Ancillary Study; Articular Range of Motion; Binding Proteins; Biological Assay; Biological Markers; Blood; Blood Banks; Blood specimen; Cessation of life; Clinical Trials; Cross-Sectional Studies; Data; Data Collection; Deposition; Development; Disease; Disease Progression; Duchenne muscular dystrophy; Edema; Enrollment; Environment; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Future; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomics; Genotype; Haplotypes; Hereditary Disease; Image; Inflammation; Inflammatory; Intervention; Intramuscular; Investments; Link; Lipids; Longitudinal Studies; Lower Extremity; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Monitor; Multicenter Studies; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Dystrophies; Natural History; Natural regeneration; Neuromuscular Diseases; Outcome Measure; Parents; Patients; Performance; Principal Investigator; Promoter Regions; Relaxation; Research Infrastructure; Role; Scanning; Serum; Serum Markers; Signal Transduction; Skeletal Muscle; Spectrum Analysis; Steroids; Testing; Therapeutic; Time; Tissues; Transforming Growth Factors; Translations; Validation; Variant; Walking; Water; age group; boys; cohort; experience; genetic variant; indexing; inflammatory marker; injured; muscular structure; novel; osteopontin; parent project; preclinical study; premature; programs; public health relevance; response; therapeutic development; trend

Project Summary/Abstract This is an ancillary application to the parent project R01AR056973, "Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy". Duchenne muscular dystrophy (DMD) is one of the most devastating genetically linked neuromuscular diseases and affects one in 3,500-6,000 boys. Dystrophic muscle is fragile and experiences repeated cycles of muscle fiber degeneration and regeneration, before they are ultimately replaced by intramuscular fat and fibrosis. Since new experimental therapeutic strategies are targeting the suppression of inflammation and fibrosis, this ancillary study proposes to examine the link between magnetic resonance (MR) markers and genetic modifiers of fibrosis and inflammation, specifically Ltbp4 and osetopontin. A significant challenge for MR has been the quantification of fibrosis, characterized by short T2 values, which may not be visualized by standard MRI. In this ancillary study, we will add novel MR acquisitions that are sensitive to short T2 to monitor fibrosis in the large cohort of boys with DMD enrolled in the parent study. The central hypothesis of this ancillary study is that MR markers of muscle fibrosis and inflammation are linked to LTBP4 and osteopontin genetic variants and disease progression in DMD. To test this hypothesis we propose the following three aims. In Aim 1 additional MR scans will be added to the parent study to capture and quantify MRI signals with extremely short T2 values to monitor fibrosis. Scans will be performed at baseline for cross-sectional analysis in year 1 of the ancillary study and correlated with latent transforming growth factor TGF¿ binding protein-4 (LTBP4) polymorphisms derived from patient fibroblast collected as part of the parent project. In Aim 2, we will perform additional quantitative measures of muscle water relaxation and water content (edema) and relate these to differences in serum profiles of inflammatory markers and polymorphisms in the osteopontin gene. Finally in Aim 3 we will take advantage of the longitudinal functional and MR data collection in the parent project to study the relationship between the 1-year change in MR markers of fibrosis, lipid deposition, and loss in functional performance and its association with LTBP4/Osteopontin genotype. This is a time-sensitive application to leverage the investment in infrastructure, access to enrolled boys with DMD, and extensive data collection in the parent natural history project. The proposed ancillary study is in response to RFA-AR-13-010 and is important for the development for future clinical trials in boys with DMD.

项目总结/文摘