Immune cell regulation of the regeneration of dystrophic muscle

项目摘要。 我们研究的一个目标是了解免疫系统影响免疫系统的机制。 Duchenne肌营养不良症（DMD）的病理学。我们对肌肉萎缩症免疫生物学的理解 营养不良已经发展，明确的证据表明，对营养不良肌肉的免疫反应促进了 肌肉损伤，至少在疾病的某些阶段。这些知识使人们期望， 抑制免疫应答可以降低疾病的进展速度或严重程度。但 使用非特异性免疫抑制剂治疗肌营养不良症存在潜在的危险。免疫 系统还可以促进组织修复，使免疫抑制作为一种治疗方法得到广泛应用 可能会对肌肉健康产生净负面影响。因此，开发基于免疫的 肌营养不良症的治疗方法是缺乏对各种各样的，复杂的， 营养不良的肌肉和免疫系统之间的动态相互作用。 我们研究的重点将是确定免疫细胞在髓系中的作用， 肌肉再生和测试新的假设，骨髓细胞生产的蛋白Klotho驱动 再生我们将使用DMD的mdx小鼠模型实现以下目标： 目标1.测试M2巨噬细胞表达的一种名为Klotho的蛋白质促进 营养不良肌肉的再生。 目标2.测试Klotho调节营养不良小鼠肌肉炎症的假设。 目标3.检验Klotho表达增加减少重度肌肉萎缩症病理学的假设。 由肌营养不良蛋白和肌营养不良蛋白突变引起的营养不良。 总的来说，这些发现将提供关于巨噬细胞在肿瘤中作用的新认识。 营养不良肌肉的再生。我们预计，这些信息可以为未来提供基础。 可以利用免疫系统对营养不良肌肉的促再生影响的工作 来减少DMD的发病率。

Project summary. A goal of our research is to understand mechanisms through which the immune system influences the pathology of Duchenne muscular dystrophy (DMD). As our understanding of the immunobiology of muscular dystrophy has advanced, clear evidence shows that the immune response to dystrophic muscle promotes muscle damage, at least in some stages of the disease. That knowledge has led to the expectation that suppressing the immune response can reduce the rate of progress or severity of the disease. However, a potential danger of using non-specific immunosuppressants to treat muscular dystrophy exists. The immune system can also promote tissue repair so that the broad application of immunosuppression as a treatment may have a net, negative effect on muscle health. Thus, a critical barrier to developing immune-based treatments for muscular dystrophy is the shortage of mechanistic knowledge of the diverse, complex and dynamic interactions between dystrophic muscle and the immune system. The focus of our study will be to determine the role of immune cells in the myeloid lineage for regulating muscle regeneration and test the novel hypothesis that myeloid cell production of the protein Klotho drives regeneration. We will pursue the following aims, using the mdx mouse model of DMD: Aim 1. Test the hypothesis that a protein expressed by M2 macrophages, called Klotho, promotes regeneration of dystrophic muscle. Aim 2. Test the hypothesis that Klotho modulates muscle inflammation in dystrophic mice. Aim 3. Test the hypothesis that increased expression of Klotho reduces pathology in severe muscular dystrophy caused by mutation of both dystrophin and utrophin. Collectively, these findings will provide new understandings concerning the role of macrophages in the regeneration of dystrophic muscle. We anticipate that this information can provide the foundation for future work in which the pro-regenerative influences of the immune system on dystrophic muscle can be exploited to reduce the pathology of DMD.