Immune cell regulation of the regeneration of dystrophic muscle

免疫细胞对营养不良性肌肉再生的调节

• 批准号: 9118073
• 负责人: JAMES G TIDBALL
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118073
• 关键词: Affect; Biological Assay; Bone Marrow Cell Transplantation; Cells; Complex; Disease; Duchenne muscular dystrophy; Dystrophin; Fibrosis; Foundations; Functional disorder; Future; Goals; Health; Immune; Immune Targeting; Immune response; Immune system; Immunobiology; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory Response; Investigation; Knockout Mice; Knowledge; Learning; Longevity; Macrophage Activation; Mus; Muscle; Muscle function; Muscular Atrophy; Muscular Dystrophies; Mutant Strains Mice; Mutation; Myelogenous; Myeloid Cells; Natural regeneration; Pathology; Phenotype; Production; Proteins; Recombinants; Regulation; Research; Role; Severity of illness; Site; Staging; Testing; Therapeutic; Transgenes; Transgenic Mice; Utrophin; Wasting Syndrome; Work; base; cytokine; cytotoxicity; design; expectation; genetic manipulation; improved; klotho protein; macrophage; mdx mouse; mouse model; muscle regeneration; novel; regenerative; satellite cell; tissue repair; transcriptome; transgene expression

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：我们研究的一个目标是了解免疫系统影响杜氏肌营养不良症（DMD）病理学的机制。随着我们对肌营养不良症免疫生物学的了解不断深入，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。这一知识导致人们期望抑制免疫反应可以降低疾病的进展速度或严重程度。然而，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，因此广泛应用免疫抑制作为治疗可能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治疗的关键障碍是缺乏营养不良肌肉和免疫系统之间多样、复杂和动态相互作用的机制知识。我们研究的重点将是确定免疫细胞在髓系中调节肌肉再生的作用，并测试髓系细胞产生Klotho蛋白驱动再生的新假设。我们将使用DMD的mdx小鼠模型追求以下目标：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再生的假设。目标2.测试Klotho调节营养不良小鼠肌肉炎症的假设。目标3.测试Klotho表达增加减少由肌营养不良蛋白和肌营养不良蛋白突变引起的严重肌营养不良症的病理的假设。总的来说，这些发现将提供关于巨噬细胞在营养不良肌肉再生中的作用的新认识。我们预计，这些信息可以为未来的工作提供基础，在未来的工作中，免疫系统对营养不良肌肉的促再生影响可以被利用来减少DMD的病理。