Role of PPAR-delta in Duchenne Muscular Dystrophy

PPAR-δ 在杜氏肌营养不良症中的作用

• 批准号: 7114001
• 负责人: VIHANG A NARKAR
• 金额: $ 5.04万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 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/7114001
• 关键词: Duchenne muscular dystrophy; biomarker; cell morphology; cytoskeletal proteins; diaphragm; disease /disorder model; dystrophin; gastrocnemius muscle; gene expression; gene induction /repression; genetically modified animals; immunocytochemistry; inhibitor /antagonist; laboratory mouse; muscle contraction; muscle disorder chemotherapy; muscle function; muscle pharmacology; peroxisome proliferator activated receptor; polymerase chain reaction; postdoctoral investigator; protein isoforms; protein localization; receptor expression; stimulant /agonist; striated muscles

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。