Targeting Myostatin Activation for Treatment of Muscular Dystraphy

靶向肌肉生长抑制素激活治疗肌肉萎缩症

• 批准号: 7648210
• 负责人: SE-JIN LEE
• 金额: $ 48.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648210
• 关键词: Animals; Binding Proteins; Blood; Cattle; Complex; Endopeptidases; Engineering; FSTL3 gene; Family; Family member; Genes; Goals; Growth; Human; Hyperplasia; Hypertrophy; Metalloproteases; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Mutation; Patients; Peptide Hydrolases; Proteins; Role playing therapy; Signal Transduction; Skeletal Muscle; Therapeutic Agents; Transforming Growth Factors; in vivo; insight; member; myostatin; novel therapeutics; research study

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.

肌生长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