Role of TGF-B1 in Duchenne Muscular Dystrophy

杜氏肌营养不良症（DMD）是最常见的遗传性疾病之一，每3500人中就有1人患病 男性出生。其特征是进行性肌无力和过早死亡， 呼吸衰竭它是由X染色体上有缺陷的肌营养不良蛋白基因引起的， 肌纤维变性、坏死、再生及明显的继发性炎症和纤维化。 虽然基因或细胞替代可能提供最终的治愈，但这些方法目前还没有 可行因此，改变继发性发病机制，炎症和纤维化，可以提供一种治疗方法。 阻止疾病进展的重要替代方法。转化生长因子-β 1（TGF-β 1）， 是一种广泛表达的多功能细胞因子，已被证明是细胞增殖的关键调节因子。 生长和分化、炎症和纤维化。已经表明，TGF-β 1的水平 在DMD肌肉活组织检查中，表达上调并且似乎与纤维化相关。阻断TGF- B1功能可以减少mdx小鼠膈肌中I型胶原mRNA的表达，mdx小鼠是一种 DMD本研究建议使用体内功能丧失和功能获得的方法来测试我们的 一个中心假设，即TGF-β 1在调节炎症和纤维化中起重要作用， 肌营养不良蛋白缺陷小鼠、mdx和dko小鼠。我们提出了四个具体目标：具体目标1将 确定TGF-β 1、2、3及其受体（I、II、III）的表达与炎症的相关性， 在mdx和dko小鼠中横膈膜和后肢肌肉中的纤维化。具体目标2将决定 阻断TGF-β 1功能对mdx膈肌纤维化的影响。具体目标3将决定影响 免疫缺陷mdx小鼠膈肌纤维化中TGF-β 1表达的缺失。具体目标4将 确定TGF-β 1过表达对dko小鼠疾病进展和存活的影响。的 拟议的研究将使我们更好地了解TGF-β 1在细胞内的动态作用， 在体内与肌营养不良蛋白缺乏相关的肌肉炎症和纤维化。获得的知识 这些研究可能会导致开发一种新的治疗方法，靶向TGF-β 1 表达以改善DMD患者的炎症和纤维化。

Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases affecting 1 in 3,500 male births. It is characterized by progressive muscle weakness and premature death from cardiac and respiratory failure. It is caused by a defective dystrophin gene on the X chromosome that results in , myofiber degeneration, necrosis, regeneration, and remarkable secondary inflammation and fibrosis. Although gene or cell replacement may provide ultimate cure, these approaches are currently not feasible. Therefore modifying secondary pathogenesis, inflammation and fibrosis, may provide an important alternative approach to halt disease progression. Transforming growth factor-beta 1 (TGF-B1), a widely expressed multifunctional cytokine, has been demonstrated to be a critical regulator for cell growth and differentiation, inflammation, and fibrosis. It has been shown that the level of TGF-B1 expression is upregulated and appears to correlate with fibrosis in DMD muscle biopsies. Blocking TGF- B1 function can reduce collagen I mRNA expression in the diaphragm of mdx mice, a mouse model of DMD. This study proposes to use in vivo loss-of-function and gain-of-function approaches to test our central hypothesis that TGF-B1 plays an important role in regulating inflammation and fibrosis in dystrophin deficient mice, mdx and dko mice. We propose four specific aims: Specific aim 1 will determine the correlation of expression of TGF-B1, 2, 3 and their receptors (I, II, III) with inflammation and fibrosis in diaphragm and hind limb muscles in mdx and dko mice. Specific aim 2 will determine the impact of blocking TGF-B1 function on mdx diaphragm fibrosis. Specific aim 3 will determine the impact of loss of TGF-B1 expression on diaphragm fibrosis in immune-deficient mdx mice. Specific aim 4 will determine the impact of overexpression of TGF-B1 on disease progression and survival of dko mice. The proposed studies will provide us with a better understanding of the dynamic roles that TGF-B1 plays in vivo in the muscle inflammation and fibrosis associated with dystrophin deficiency. Knowledge gained from these studies may lead to development of a novel therapeutic approach that targets TGF-B1 expression to ameliorate inflammation and fibrosis in patients with DMD.