Targeting Myostatin Activation for Treatment of Muscular Dystraphy

肌生成抑制素是一种转化生长因子-LI家族成员，作为肌肉的负调节因子 增长结果，缺乏肌肉生长抑制素的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结合增加肌肉也发生在牛 以及肌肉生长抑制素基因自然发生突变的人类。这些发现提高了 能够阻断肌生长抑制素活性的药剂可能有效增加肌肉质量， 肌肉萎缩症患者的力量。本建议的总体目标是确定战略， 开发靶向肌生长抑制素活性的治疗剂。已知肌肉生长抑制素以一种 与其他蛋白质（包括肌生长抑制素前肽、FLRG和Gasp-1）形成的潜伏、无活性复合物。的 与前肽的复合物可以通过前肽的蛋白水解裂解而被激活，所述蛋白水解裂解由前肽的 金属蛋白酶的BMP-1/tolloid家族。负责激活潜伏性肌生长抑制素的特异性蛋白酶， vivo是未知的。各种肌生长抑制素结合蛋白中的每一种所起的调节作用也不相同。 知道的该建议的主要目标是阐明肌生长抑制素活性被抑制的机制。 细胞外调节。具体目标是：产生和表征小鼠，其中基因编码 BMP-1/tolloid家族的每个成员在骨骼肌中单独或组合地被破坏 并表征肌生长抑制素与其已知结合蛋白的相互作用。的结果予以 实验应该为肌生长抑制素活性如何正常调节提供重要的见解，从而 为鉴定阻断肌生长抑制素信号传导的策略提供了有价值的信息。如果成功，这些 实验将为开发新的治疗剂提供框架， 肌肉萎缩症患者的肿块。

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.