cGMP Phosphodiesterase Inhibitors in a Mouse Model of Duchenne Muscular Dystrophy

杜氏肌营养不良症小鼠模型中的 cGMP 磷酸二酯酶抑制剂

基本信息

批准号：
7470950
负责人：
STANLEY C FROEHNER
金额：
$ 20.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470950
关键词：
Affect Animals Anterior Anti-Inflammatory Agents Anti-inflammatory Biology Blood flow Caliber Cardiovascular system Cell Nucleus Cell Therapy Clinical Clinical Trials Complex Count Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclic Nucleotides Defect Deterioration Disease Disease Progression Drug Delivery Systems Duchenne muscular dystrophy Dyes Dystrophin Elements Enzymes Equipment Erectile dysfunction Evans blue stain Failure Fatigue Fiber Fibrosis Follistatin Functional disorder Funding Genes Genetic Golgi Apparatus Grant Growth Guanylate Cyclase Health Heart Hypertrophy Human Hypertension Immunoblotting Immunofluorescence Immunologic Inflammation Inflammatory Injury Intermittent Claudication Knockout Mice Laboratories Lead Longevity Measurement Measures Mediating Methods Modeling Molecular Abnormality Mus Muscle Muscle Fibers Muscular Dystrophies Mutation Natural regeneration Necrosis Nitric Oxide Numbers Pathology Pathway interactions Pharmaceutical Preparations Phenotype Phosphodiesterase Inhibitors Physiology Process Program Research Project Grants Property Proteins Protocols documentation Publishing Pulmonary Hypertension Purpose Quality of life RNA Splicing Recurrence Regulation Research Resistance Respiratory Diaphragm Right ventricular structure Role Running Sarcolemma Severities Severity of illness Signal Pathway Signal Transduction Skeletal Muscle Staging Stroke Testing Therapeutic Time Treatment Protocols Universities Utrophin Washington base drinking water drug efficacy experience gene replacement human disease improved inhibitor/antagonist mdx mouse mouse model muscle necrosis phosphoric diester hydrolase pressure repaired sildenafil therapeutic gene therapy development uptake

项目摘要

DESCRIPTION (provided by applicant): Despite the fact that muscular dystrophies are caused by mutations in numerous different genes, they share several common features: loss of muscle mass, inflammation and fibrosis, and progressive failure to regenerate. Ultimately, gene replacement or correction will lead to cures, but routine application of these approaches is likely to be decades away. The development of treatments that slow the progression of muscle degeneration will improve the quality and length of life and permit treatment at more advanced stages of the disease. In this application, we propose to test the efficacy of cyclic nucleotide phosphodiesterase (PDE) inhibitors in slowing the degeneration process in dystrophic muscle. PDE inhibitors are key modulators of cyclic GMP (cGMP) mediated pathways and have proven to be effective drug targets in treating several human diseases, including inflammatory airway diseases, intermittent claudication, recurrent stroke and erectile dysfunction. PDE inhibitors, particularly those targeted at PDE5, reduce cardiac hypertrophy and fibrosis in a pressure induced mouse model. We have new evidence that a nitric oxide-stimulated cGMP pathway on the Golgi complex is disrupted in skeletal muscle of mdx mice. We will test the hypothesis that administration of PDE inhibitors to mdx mice will slow the progression of skeletal muscle degeneration. Preliminary evidence suggests that sildenafil, a PDE5 inhibitor, administered in the drinking water improves the dystrophic phenotype. Ultimately, gene or cell therapy approaches combined with drug treatments that stimulate muscle growth and repair by modulation of cGMP pathways could be an effective treatment for muscular dystrophies of various genetic origins. The research proposed here will test FDA-approved drugs (phosphodiesterase inhibitors) for their ability to slow the progression of muscle degeneration in muscular dystrophy. If efficacious, these drugs could quickly be tested for this use in humans since they have already been approved for treatment of other diseases. They may be useful in many different types of muscular dystrophies by improving muscle health and prolonging survival time.

描述（由申请人提供）：尽管肌肉营养不良是由许多不同基因突变引起的，但它们具有多种常见特征：肌肉质量的丧失，炎症和纤维化以及逐渐失效的再生。最终，基因置换或校正将导致治愈，但是这些方法的常规应用可能会在数十年之内。降低肌肉退化进展的治疗方法的发展将改善疾病更高级阶段的寿命和寿命，并允许治疗。在此应用中，我们建议测试循环核苷酸磷酸二酯酶（PDE）抑制剂在减慢营养不良肌肉的变性过程中的疗效。 PDE抑制剂是环状GMP（CGMP）介导的途径的关键调节剂，已证明是治疗多种人类疾病的有效药物靶标，包括炎症性气道疾病，间歇性闭合，复发性中风和勃起功能障碍。 PDE抑制剂，尤其是针对PDE5的抑制剂，在压力诱导的小鼠模型中降低了心脏肥大和纤维化。我们有新的证据表明，在MDX小鼠的骨骼肌中，高尔基体配合物上的一氧化氮刺激的CGMP途径破坏了。我们将测试以下假设：PDE抑制剂对MDX小鼠的施用将减缓骨骼肌变性的进展。初步证据表明，在饮用水中给药的PDE5抑制剂西地那非改善了营养不良的表型。最终，通过调节CGMP途径刺激肌肉生长和修复的药物治疗方法，可能是各种遗传起源的肌营养不良的有效治疗方法。此处提出的研究将测试FDA批准的药物（磷酸二酯酶抑制剂），以减缓肌肉营养不良中肌肉变性的进展。如果有效的话，这些药物可以在人类中迅速测试，因为它们已经被批准用于治疗其他疾病。通过改善肌肉健康和延长生存时间，它们可能在许多不同类型的肌肉营养不良中有用。