CELL DAMAGE AND REMODELING IN THE PROGRESSION OF DUCHENNE MUSCULAR DYSTROPHY

Duchenne肌营养不良症的细胞损伤和重塑途径 Duchenne肌营养不良症(DMD)是一种由肌营养不良蛋白缺乏引起的进行性肌肉疾病。 虽然Duchenne营养不良肌在各个年龄段都表现为肌纤维损伤和坏死，但随之而来的 DMD的肌内膜纤维化和肌肉再生逐渐衰竭被认为是下游或 肌营养不良蛋白缺乏的继发性后果。在这里，我们重点关注两个关键的组织损伤和 我们在Duchenne营养不良中显示的作为年龄函数的不同调节的重塑途径；Tolllike 受体/核因子-kB和转化生长因子-β。我们的初步研究表明，巨噬细胞、组织的激活 树突状细胞及其相关的核因子-kB途径早在新生儿期就开始出现，并保持相对稳定 在整个病理过程中活动不变。另一方面，我们显示了激活 转化生长因子途径仅在疾病过程的后期，这与肌内膜纤维化是相称的 以及新陈代谢危机。具体的目标集中在隔离每一条途径，并确定 途径调节的因果后果。目的1在体内利用两者构建转化生长因子-β途径 以及确定转化生长因子β与两个关键调节蛋白(IGFBP3和IGFBP3)相互作用的体外模型 AML1)。目标2集中在Toll样受体/核因子-kB，我们所展示的通路与 Dstrophin缺乏肌肉(8-10月龄DMD患者)的早期炎症。这一目标将剖析这一点 复杂的组织损伤和重塑途径，在其他领域带来了对这一级联反应的扩展知识 肌肉组织要承担肌肉病理。这个项目利用了肌肉方面的合作调查员的专业知识。 免疫学(Nagaraju博士)、分子病理学和肌肉重塑(Chen博士和Nagaraju博士)，以及 广泛的预先存在。该中心拥有的mRNA图谱肌肉数据集(-800个图谱)。这允许 疾病特异性的快速评估，如我们在TLR7和DMD的初步数据中所示。建议数 研究对Duchenne‘营养不良的病理生理学采取“面向路径”的方法，目标是 定义特定于人类疾病各阶段的因果通路调节，并提供基于通路的 DMD人体临床试验未来设计的目标。]

Project 2. Cell damage and remodeling pathways in Duchenne muscular dystrophy [ Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by dystrophin deficiency. Although Duchenne dystrophy muscle shows myofiber damage and necrosis at all ages, the ensuing endomysial fibrosis and gradual failure of muscle regeneration in DMD are believed to be downstream or secondary consequences of dystrophin deficiency. Here, we focus on two key tissue damage and remodeling pathways that we show differentially regulated as a function of age in Duchenne dystrophy; Tolllike receptor/NF-KB and TGF-¿. Our preliminary studies show that the activation of macrophages, tissue dendritic cells and associated NF-KB pathway occurs as early as the neonatal period and remains relatively constant in activity throughout the course of the pathology. On the other hand, we show activation of the TGF-¿ pathway only later in the disease process, and this is commensurate with both endomysial fibrosis and a metabolic crisis. The specific aims are focused on isolating each of these pathways, and determining cause/effect consequences of pathway modulation. Aim 1 builds out the TGF-¿ pathway, using both in vivo and in vitro models to determine interactions between TGF-¿, and two key modulatory proteins (IGFBP3 and AML1). Aim 2 focuses on Toll-like receptor/NF-KB, pathways that we show are commensurate with very early inflammation in dystrophin deficient muscle (8-10 month old DMD patients). This aim will dissect this complex tissue damage and remodeling pathway, bringing expanding knowledge of this cascade in other tissues to bear on muscle pathology. This project draws upon the expertise of the co-investigators in muscle immunology (Dr. Nagaraju), molecular pathology and muscle remodeling (Drs. Chen and Nagaraju), and the extensive pre-existing. mRNA profiling muscle data sets held by the Center (-800 profiles). This permits rapid assessment of disease specificity, as we show in preliminary data for TLR7 and DMD. The proposed studies take a "pathway oriented" approach to pathophysiology of Duchenne'dystrophy, with the goal of defining cause/effect pathway modulation specific for stages of the human disease, and provide pathwaybased targets for future design of human clinical trials in DMD. ]