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.

蛋白酶抑制作为肌营养不良症的可能治疗方法 该项目的主要目标是减缓骨骼肌质量和功能的损失 营养不良过程的结果。告知肌营养不良症，其中肌营养不良蛋白和 相关复合体有缺陷（例如 DMD、LGMD2C）或肌肉修复受损（例如 Dysferlin） 缺陷），肌肉蛋白质分解的激活大大提高。这个的基本假设 建议有针对性地抑制特定蛋白酶可以减少这种升高的周转率，从而导致 增加肌肉质量和力量。有许多潜在的靶点，包括细胞内 作为炎症反应、钙蛋白酶甚至特定臂的一部分而上调的蛋白酶 泛素-蛋白酶体途径。这些途径将被特定药物单独或联合抑制 肌营养不良症小鼠模型中的组合。 随着肌营养不良症的进展，由于缺乏活动，肌肉损失的速度会加快。废弃 萎缩有三个主要的根本原因；蛋白质降解增加，蛋白质减少 合成和细胞凋亡的瞬时成分。这些可能会大大加速肌肉损失 营养不良的背景。使用针对特定蛋白酶的药物可能会避免废用性萎缩 以及与营养不良本身相关的肌肉损失。这将在营养不良小鼠中进行评估 进行后肢悬吊。