PAK1 Activation Reduces Muscular Dystrophy-Mediated Fibrosis

PAK1 激活可减少肌营养不良症介导的纤维化

• 批准号: 9182217
• 负责人: JESUS GARCIA-MARTINEZ
• 金额: $ 21.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182217
• 关键词: Affect; Aging; Animals; Antibodies; Biological Models; Calcium; Calcium Signaling; Cardiac; Cell Membrane Permeability; Cells; Characteristics; Chronic; Chronic Disease; Cicatrix; Cytoskeleton; Data; Deposition; Disease; Dose; Evaluation; FDA approved; Fibroblasts; Fibronectins; Fibrosis; Healed; Heart; Immune; Immune response; Immunoblotting; Immunofluorescence Immunologic; Infiltration; Injection of therapeutic agent; Knock-out; Knockout Mice; MAPK3 gene; Mediating; Membrane; Mendelian disorder; Molecular; Morbidity - disease rate; Multiple Sclerosis; Mus; Muscle; Muscle Cells; Muscle function; Muscle satellite cell; Muscular Dystrophies; Mutant Strains Mice; Myocardium; Natural regeneration; Nature; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Prevention; Prevention Protocols; Protocols documentation; Publications; Recovery; Recovery of Function; Regimen; Relaxation; Respiratory Diaphragm; Sclerosis; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Small Interfering RNA; Sphingosine; Stem cells; TNF gene; Technology; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Work; analog; connective tissue growth factor; effective therapy; gamma Sarcoglycan; healing; insight; interstitial; mortality; mouse model; muscular dystrophy mouse model; new therapeutic target; periostin; repaired; research study; satellite cell; skeletal; treatment duration

Fibrosis is a pathogenic occurrence in many diseases. In the chronic disease muscular dystrophy, fibrosis is particularly devastating as it impedes; function, recovery and treatment delivery. Fibrosis impedes function because it is non-contractile but more importantly for diaphragm and cardiac tissue fibrosis slows relaxation, a key component of optimal muscle function and for cardiac tissue cannot transmit a contraction impulse. Recovery is hampered by fibrosis because muscle stem cells – satellite cells – are exquisitely sensitive to their niche and fibrosis destroys the niche. Fibrosis also decreases treatments which cannot progress to their sites of action due to excessive fibrosis. We have statistically significant preliminary data that 3 week treatment with the PAK1 activator FTY-720 drastically inhibits fibrosis in all three muscle tissues tested. We now plan to identify the best dose and treatment regime to inhibit murine muscular dystrophy. We will also investigate if the treatment alleviates other muscular dystrophy phenotypes; membrane permeability, aberrant calcium signaling, and excessive immune infiltration. Finally the mechanisms of action will be investigated. These results will greatly aid patients with muscular dystrophy as FTY-720 is already FDA approved for multiple sclerosis.

纤维化是许多疾病的致病因素。在慢性疾病肌肉