Targeting Myostatin Activation for Treatment of Muscular Dystraphy

肌肉生长抑制素是一种转化生长因子家族成员，对肌肉起负向调节作用。 成长。因此，缺乏肌肉生长抑素的转基因小鼠的肌肉质量大约是正常动物的两倍 肌肉纤维增生和肥大的组合。两头牛的肌肉也都增加了。 以及肌肉抑制素基因自然发生突变的人类。这些发现提高了 能够阻断肌肉抑制素活性的药物可能有效地增加肌肉质量和 肌营养不良症患者的力量。这项提案的总体目标是确定以下战略 开发针对肌肉生长抑素活性的治疗药物。已知肌肉生长抑制素在血液中循环 潜伏的，非活性的与其他蛋白质的复合体，包括肌肉生长抑素前肽、Flrg和GASP-1。这个 与前肽的复合体可以通过前肽的蛋白水解性切割而被激活 BMP-1/Tolloid金属蛋白酶家族。负责激活潜伏的肌肉生长抑素的特定蛋白酶 活体尚不清楚。不同的肌肉抑制素结合蛋白所起的调节作用也不是 为人所知。这项建议的主要目标是阐明肌肉生长抑素活性的机制。 细胞外调节。其具体目标是：培育和鉴定编码基因的小鼠 BMP-1/Tolloid家族的每个成员在骨骼肌中单独或组合被破坏 并研究肌肉生长抑制素与其已知结合蛋白的相互作用。这些研究的结果 实验应该为肌肉抑制素活动的正常调节提供重要的见解，从而 为确定阻断肌肉抑制素信号转导的策略提供有价值的信息。如果成功，这些 实验将为开发能够增加肌肉的新治疗剂提供框架 肌营养不良症患者的肿块。

Myostatin is a transforming growth factor-li family member that acts as a negative regulator of muscle growth. Mice engineered to lack myostatin have about twice the muscle mass of normal animals as a result of a combination of muscle fiber hyperplasia and hypertrophy. Increased muscling also occurs in both cattle and humans with naturally occurring mutations in the myostatin gene. These findings have raised the possibility that agents capable of blocking myostatin activity may be effective in increasing muscle mass and strength in patients with muscular dystrophy. The overall aim of this proposal is to identify strategies for developing therapeutic agents targeting myostatin activity. Myostatin is known to circulate in the blood in a latent, inactive complex with other proteins, including the myostatin propeptide, FLRG, and Gasp-1. The complex with the propeptide can be activated by proteolytic cleavage of the propeptide by members of the BMP-1/tolloid family of metalloproteases. The specific protease responsible for activating latent myostatin in vivo is not known. The regulatory roles played by each of the various myostatin binding proteins are also not known. The major goal of this proposal is to elucidate the mechanisms by which myostatin activity is regulated extracellularly. The specific aims are: to generate and characterize mice in which genes encoding each member of the BMP-1/tolloid family are disrupted either individually or in combination in skeletal muscle and to characterize the interactions of myostatin with its known binding proteins. The results of these experiments should provide important insights into how myostatin activity is normally regulated and thereby provide valuable information for identifying strategies for blocking myostatin signaling. If successful, these experiments will provide the framework for developing new therapeutic agents capable of increasing muscle mass in patients with muscular dystrophy.