Protease Inhibition as Possible therapy for Muscular Dystrophy

蛋白酶抑制作为肌营养不良症的可能治疗方法

• 批准号: 7648211
• 负责人: H Lee Sweeney
• 金额: $ 47.05万
• 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/7648211
• 关键词: Address; Apoptosis; Apoptotic; Atrophic; Attenuated; Calcium; Calpain; Class; Complex; Coupled; DYSF gene; Defect; Disuse Atrophy; Drug usage; Dystrophin; Endopeptidases; Extracellular Matrix; Goals; Growth; Hindlimb Suspension; Inflammatory Response; Insulin-Like Growth Factor I; Intervention; Knockout Mice; Lead; Leupeptins; Mediating; Mus; Muscle; Muscle Proteins; Muscle function; Muscular Atrophy; Muscular Dystrophies; Numbers; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Predisposition; Process; Protease Inhibitor; Proteasome Inhibitor; Protein Biosynthesis; Proteins; Rate; Sarcoglycans; Serine Protease; Signal Pathway; Signal Transduction; Skeletal Muscle; Ubiquitin; Upper arm; base; experience; extracellular; falls; inhibitor/antagonist; leupeptin; mouse model; multicatalytic endopeptidase complex; muscular dystrophy mouse model; myostatin; prevent; protein degradation; repaired; satellite cell; therapeutic target; ubiquitin ligase

Protease inhibition as possible therapy for muscular dystrophy The major goals of this project are to slow the loss of skeletal muscle mass and function that occurs as a consequence of the dystrophic process. Informs of muscular dystrophy in which the dystrophin and associated complex are defective (e.g. DMD, LGMD2C) or in which muscle repair is impaired (e.g. dysferlin defects), activation of muscle protein breakdown is greatly elevated. The fundamental hypothesis of this proposal is that targeted inhibition of specific proteases can reduce this elevated turnover, leading to increased muscle mass and strength. There are a number of potential targets, including intracellular proteases that are up-regulated as part of the inflammatory response, calpain and even specific arms of the ubiquitin-proteosome pathway. These pathways will be inhibited with specific drugs, alone and in combination in mouse models of muscular dystrophies. As muscular dystrophy progresses, the rate of loss of muscle accelerates as inactivity is imposed. Disuse atrophy has at its basis three major underlying causes; increased protein degradation, decreased protein synthesis and a transient component of apoptosis. These likely will greatly accelerate muscle loss on a dystrophic background. Using drugs to target specific proteases may lead to a sparing of the disuse atrophy as well as the muscle loss associated with the dystrophy itself. This will be evaluated in dystrophic mice subjected to hindlimb suspension.

蛋白酶抑制作为治疗肌肉萎缩症的可能方法