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.

蛋白酶抑制是肌营养不良的疗法 该项目的主要目标是减慢骨骼肌质量和功能的损失 营养不良过程的结果。告知肌营养不良的肌营养不良症，其中肌营养不良蛋白和 相关复合物有缺陷（例如DMD，LGMD2C）或肌肉修复受损（例如Dysferlin 缺陷），肌肉蛋白崩溃的激活大大升高。这个基本假设 建议是针对特定蛋白酶的有针对性抑制可以减少该高架营业额，从而导致 增加肌肉质量和力量。有许多潜在目标，包括细胞内 作为炎症反应，钙蛋白酶甚至特定臂的一部分上调的蛋白酶 泛素 - 蛋白质途径。这些途径将被特定药物抑制 肌肉营养不良的小鼠模型中的组合。 随着肌肉营养不良的进展，随着肌肉的损失率加速了，随着不活动的施加。废弃 萎缩在其基础上有三个主要的基本原因；蛋白质降解增加，蛋白质降低 合成和凋亡的瞬态成分。这些可能会大大加速 营养不良的背景。使用药物靶向特定的蛋白酶可能导致残留萎缩的保留 以及与营养不良本身有关的肌肉损失。这将在营养不良的小鼠中评估 受到后肢停职。