Role of PPAR-delta in Duchenne Muscular Dystrophy

PPAR-δ 在杜氏肌营养不良症中的作用

基本信息

批准号：
7250216
负责人：
VIHANG A NARKAR
金额：
$ 5.48万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7250216
关键词：
Acute Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Biological Assay Biological Markers Breeding C Fiber Calcium Characteristics Contracts Creatine Kinase Cytoplasm Duchenne muscular dystrophy Dystroglycan Enzymes Exclusion Fatigue Fellowship Fiber Gastrocnemius Muscle Gene Expression Homeostasis Individual Inflammation Inflammatory Inflammatory Response Interleukin-15 Interleukin-6 Measures Membrane Morphology Mus Muscle Muscular Dystrophies Myogenin Myoglobin Myopathy Names Nuclear Receptors PPAR delta PTGS2 gene Pathology Performance Physiological Predisposition Property Proteins Receptor Activation Research Proposals Resistance Respiratory Diaphragm Rodent Model Role Running Ryanodine Receptor Calcium Release Channel Sarcoglycans Serum Skeletal Muscle Staining method Stains Testing Time Transgenic Mice Transgenic Organisms Treadmill Tests Troponin I Utrophin Week cyclooxygenase 2 cytokine day design dystrobrevin improved macrophage mdx mouse myostatin research study

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscles express multiple nuclear receptors. However, their role in muscular dystrophy is unknown. Recently, we found that transgenic mice over-expressing nuclear receptor PPAR-delta in skeletal muscles ran twice as long and as far as non-transgenic mice on a treadmill [Transgenic/non-transgenic; time: 140 min/80 min; distance: 1800 m/800 m]. Such an improvement in skeletal muscle performance on activating PPAR-delta may be beneficial in dystrophic muscles, which are characterized by weakness and fatigue. In this proposal we will test the hypothesis that activation of PPAR-delta decreases the pathology of Duchenne muscular dystrophy (DMD). All the experiments related to the hypothesis will be performed in mdx mice, a rodent model of DMD. In brief, we will measure the suppressive effect of both PPAR-delta agonist (GW1516) treatment and muscle specific PPAR-delta over-expression on the pathological biomarkers of DMD in mdx mice at the level of muscle morphology, gene expression and contractile properties. The results from our study will reveal whether PPAR-delta is an appropriate target to counteract DMD as well as whether an orally active PPAR-delta agonist can decrease the pathology of DMD.

描述（由申请人提供）：骨骼肌表达多种核受体。然而，它们在肌营养不良症中的作用尚不清楚。最近，我们发现骨骼肌中过表达核受体PPAR-δ的转基因小鼠在跑步机上跑的时间和距离是非转基因小鼠的两倍[转基因/非转基因；时间：140分钟/80分钟；距离：1800 m/800 m]。这种通过激活 PPAR-δ 来改善骨骼肌性能可能对以虚弱和疲劳为特征的营养不良性肌肉有益。在本提案中，我们将检验以下假设：PPAR-δ 的激活可降低杜氏肌营养不良症 (DMD) 的病理学。所有与该假设相关的实验都将在 mdx 小鼠（一种 DMD 啮齿动物模型）中进行。简而言之，我们将在肌肉形态、基因表达和收缩特性水平上测量 PPAR-δ 激动剂 (GW1516) 治疗和肌肉特异性 PPAR-δ 过表达对 mdx 小鼠 DMD 病理生物标志物的抑制作用。我们的研究结果将揭示 PPAR-δ 是否是对抗 DMD 的合适靶点，以及口服活性 PPAR-δ 激动剂是否可以减轻 DMD 的病理。