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：
7433187
负责人：
VIHANG A NARKAR
金额：
$ 5.67万
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/7433187
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）：骨骼肌表达多个核受体。但是，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度表达核受体PPAR-delta的转基因小鼠的长度是跑步机上的非转基因小鼠的两倍，并且是跑步机上的非转基因小鼠。时间：140分钟/80分钟；距离：1800 m/800 m]。激活PPAR-DELTA的骨骼肌性能的这种改善可能对营养不良的肌肉有益，其特征是虚弱和疲劳。在此提案中，我们将检验以下假设：PPAR-DELTA的激活降低了Duchenne肌肉营养不良（DMD）的病理。与假设相关的所有实验将在DMD的啮齿动物模型MDX小鼠中进行。简而言之，我们将测量PPAR-DELTA激动剂（GW1516）治疗和肌肉特异性PPAR-DELTA对MDX小鼠DMD病理生物标志物在肌肉形态，基因表达和收缩特性水平上的病理生物标志物的抑制作用。我们研究的结果将揭示PPAR-DELTA是否是抵消DMD的合适靶标，以及口服活跃的PPAR-DELTA激动剂是否可以降低DMD的病理。