Role of TGF-B1 in Duchenne Muscular Dystrophy

Duchenne肌营养不良症(DMD)是最常见的遗传性疾病之一，每3,500人中就有1人患病 男性出生。它的特点是进行性肌肉无力和过早死亡的心脏和 呼吸衰竭。它是由X染色体上的营养不良蛋白基因缺陷引起的， 肌纤维变性、坏死、再生，并有明显继发性炎症和纤维化。 尽管基因或细胞置换可能提供最终的治愈方法，但这些方法目前还不能 可行。因此，改变继发性发病机制、炎症和纤维化可能提供一种 阻止疾病进展的重要替代方法。转化生长因子-β1(TGF-β1)， 一种广泛表达的多功能细胞因子，已被证明是细胞的关键调节因子。 生长和分化、炎症和纤维化。已有研究表明，血清转化生长因子-β1水平 在DMD肌肉活检中，表达上调，似乎与纤维化有关。阻断转化生长因子-2 B1功能可降低MDX小鼠横隔区I型胶原mRNA的表达 DMD。这项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 中心假设，转化生长因子-β1在调节炎症和纤维化中发挥重要作用 Dystrophin缺陷小鼠、mdx和dko小鼠。我们提出四个具体目标：具体目标1将 确定转化生长因子-β1、2、3及其受体I、II、III的表达与炎症和 Mdx和dko小鼠的横隔肌和后肢肌肉纤维化。具体目标2将决定 阻断转化生长因子-β1功能对MDX横隔膜纤维化的影响具体目标3将决定影响 在免疫缺陷mdx小鼠的横隔膜纤维化中，转化生长因子-β1的表达缺失。具体目标4将 确定过度表达转化生长因子-β1对dKO小鼠疾病进展和生存的影响。这个 拟议的研究将使我们更好地理解转化生长因子-β1在 体内肌肉炎症和纤维化与肌营养不良蛋白缺乏症相关。获得的知识 可能导致开发一种针对转化生长因子-β1的新的治疗方法 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.