TGFβ信号通路在FBN1基因突变导致马凡综合症骨骼肌萎缩中的作用机制研究

The unbalance of injury and regeneration in skeletal muscle leads to skeletal muscle atrophy，which induces the dysmotility. The muscle atrophy was one of the complication of Marfan syndrome, but the underlined mechanism is remained unclear. The causative gene FBN1 could regulate the activity of TGFβ signaling pathway. The genes of TGFβ family were up-regulated after muscle injury, and regulate the proliferation and differentiation of myoblast. We have previously found that the regeneration of FBN1 C1039G mutation transgenic mice was impaired after muscle injury. In this study, we will examine the muscle regeneration, interstitial fibrosis and inflammation response of aging and acute injury muscle from WT and FBN1 mutation transgenic mice, and further examine the activity of TGFβ signaling pathway and use the neutralization antibody to clarify the key molecular mechanism of Marfan syndrome muscle atrophy, which will provide novel target to the prevention of muscle atrophy complication of Marfan syndrome.

骨骼肌损伤和修复失衡导致骨骼肌萎缩和运动功能障碍。马凡综合征患者伴有骨骼肌萎缩的临床表现，但其发病机制尚不清楚。马凡综合征主要致病基因FBN1的主要功能是影响炎症因子TGFβ活性，而TGFβ家族细胞因子在骨骼肌损伤时表达上调，并且调节肌卫星干细胞的增殖和分化。前期研究发现FBN1 C1039G点突变转基因小鼠在急性损伤后再生受损。据此，提出科学假设：马凡患者FBN1基因突变影响TGFβ信号通路活性，导致促修复的骨骼肌微环境发生变化，抑制肌卫星细胞的增殖或分化能力，造成骨骼肌修复的稳态失衡，发生骨骼肌萎缩。我们拟使用马凡综合征致病基因FBN1转基因小鼠，在衰老和急性骨骼肌损伤模型中观察肌纤维再生，间质纤维化和炎症反应的情况，并进一步检测TGFβ分子及其相关信号通路在骨骼肌中的活性变化，并给予中和抗体来探索马凡综合征骨骼肌萎缩的分子机制，从而为寻找延缓或避免骨骼肌萎缩发生的治疗靶点提供新思路。