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

Duchene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，测试新的高度特异的抗炎药物，用于潜在的肌肉营养不良的临床治疗。在小鼠身上进行长期研究，充分评估这些抗炎药的益处是至关重要的。其中两种药物(Enbrel和Remicade)已经广泛用于炎症性疾病的临床治疗，由于其高度的作用特异性和相对较少的副作用，为治疗DMD患者提供了有吸引力的选择。我们已经证明，这两种药物都有显着的保护作用，并减少MDX小鼠营养不良肌肉的坏死。这些药物(以及相当于小鼠的cVIq)的好处是由于阻断了关键的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。有很多可能的途径。确定哪一条是关键途径(S)，对于设计和瞄准治疗此类致命肌肉疾病的新药至关重要。这样的信号调节是一个主要的治疗目标。为了确定TNFa作用的哪种机制导致肌肉坏死，实验将使用特定的抑制剂研究几个信号通路：抑制P53的药物Pifithin；阻断RAGE(高级糖基化终产物受体)的可溶性RAGE；以及阻断JNK(c-Jun N-末端激酶)的特定抑制肽。这些抑制剂(药物)在小鼠身上的应用，作为未来肌肉疾病的治疗方法是新颖的。这些研究将提供许多关于TNFa相关信号的新信息，这些信号与许多疾病的潜在治疗高度相关，包括肌肉萎缩，这是老龄化人口中的一个主要问题，以及废用萎缩和恶病质。

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.