Modulating interactions between TNFalpha and IGF-1 signaling pathways to reduce necrosis of dystrophic muscle

调节 TNFα 和 IGF-1 信号通路之间的相互作用以减少营养不良性肌肉坏死

• 批准号: nhmrc : 458573
• 负责人: A/Pr Marie Bogoyevitch
• 金额: $ 31.77万
• 依托单位: The University of Western Australia
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/modulating-interactions-tnfalpha-dystrophic-muscle/100578
• 关键词: Modulating; interactions; between; TNFalpha; IGF

Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attractive options for treatment of DMD patients due to their high specificity of action and relatively few side effects. We have shown that both of these drugs have a striking protective effect and reduce necrosis of dystrophic muscle in the mdx mouse. The benefits of these drugs (and the mouse equivalent cVIq) is due to blocking the action of the key pro-inflammatory cytokine Tumour Necrosis Factor-alpha (TNFa). However, the precise mechanism by which high levels of TNFa increase necrosis of dystrophic muscle is not clear. There are many possible pathways. Identifying which is the key pathway(s), is of central importance to design and target new drugs to treat such lethal muscle diseases. Such modulation of signalling is a major therapeutic goal. To determine which mechanism of TNFa action is responsible for muscle necrosis, experiments will investigate several signalling pathways using specific inhibitors: the drug Pifithrin to inhibit p53; soluble RAGE to block RAGE (Receptor for Advanced Glycation Endproducts); and specific inhibitory peptides to block JNK (c-Jun N-terminal kinase). The application of these inhibitors (drugs), in mice, as future therapies for muscle diseases is novel. These studies will provide much new information on TNFa related signalling that is highly relevant to the potential treatment of many diseases, including muscle wasting that is a major problem in the ageing population and in disuse atrophy and cachexia.

杜兴氏肌营养不良症（DMD）是一种致命的儿童疾病，主要影响男孩。这些实验将使用人类DMD的mdx小鼠模型测试新的高度特异性抗炎药物，用于肌营养不良症的潜在临床治疗。在小鼠长期研究中充分评估此类抗炎药物的益处至关重要。其中两种药物（Enbrel和Remicade）已广泛用于炎症性疾病的临床治疗，并因其高特异性作用和相对较少的副作用而为DMD患者的治疗提供了有吸引力的选择。我们已经证明，这两种药物都具有显著的保护作用，并减少mdx小鼠营养不良肌肉的坏死。这些药物（以及小鼠等效的cVIq）的益处是由于阻断了关键促炎细胞因子肿瘤坏死因子-α（TNFa）的作用。然而，高水平的TNFa增加营养不良肌肉坏死的确切机制尚不清楚。有许多可能的途径。确定哪一个是关键途径，对于设计和靶向治疗这种致命肌肉疾病的新药至关重要。这种信号传导的调节是主要的治疗目标。为了确定TNF α作用的哪种机制是导致肌肉坏死的原因，实验将使用特异性抑制剂研究几种信号传导途径：抑制p53的药物Pifithrin;阻断晚期糖基化终产物受体（Receptor for Advanced Glycation Endproducts）的可溶性抑制肽;以及阻断JNK（c-Jun N-末端激酶）的特异性抑制肽。这些抑制剂（药物）在小鼠中作为肌肉疾病的未来疗法的应用是新颖的。这些研究将提供关于TNFa相关信号传导的许多新信息，其与许多疾病的潜在治疗高度相关，包括肌肉萎缩，这是老龄化人口和废用性萎缩和恶病质中的主要问题。