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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）：尽管肌营养不良症是由许多不同基因的突变引起的，但它们具有几个共同特征：肌肉质量损失，炎症和纤维化，以及进行性再生失败。最终，基因替换或修正将导致治愈，但这些方法的常规应用可能需要几十年的时间。减缓肌肉退化进展的治疗方法的发展将提高生活质量和寿命，并允许在疾病的更晚期阶段进行治疗。在本申请中，我们提出测试环核苷酸磷酸二酯酶（PDE）抑制剂在减缓营养不良肌肉的变性过程中的功效。 PDE抑制剂是环GMP（cGMP）介导的途径的关键调节剂，并且已被证明是治疗多种人类疾病的有效药物靶标，包括炎性气道疾病、间歇性跛行、复发性中风和勃起功能障碍。PDE抑制剂，特别是靶向PDE 5的那些，在压力诱导的小鼠模型中减少心脏肥大和纤维化。我们有新的证据表明，一氧化氮刺激的cGMP途径高尔基复合体被破坏的mdx小鼠骨骼肌。我们将检验向mdx小鼠施用PDE抑制剂将减缓骨骼肌变性进展的假设。初步证据表明，西地那非，一种PDE5抑制剂，在饮用水中给药可改善营养不良表型。最终，基因或细胞治疗方法与通过调节cGMP途径刺激肌肉生长和修复的药物治疗相结合，可能是各种遗传来源的肌营养不良症的有效治疗方法。这里提出的研究将测试FDA批准的药物（磷酸二酯酶抑制剂）减缓肌营养不良症肌肉变性进展的能力。如果有效，这些药物可以很快在人类中进行测试，因为它们已经被批准用于治疗其他疾病。它们可以通过改善肌肉健康和延长生存时间来治疗许多不同类型的肌营养不良症。