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 该项目的主要目标是减缓骨骼肌质量和功能的丧失， 营养不良过程的结果。肌营养不良症的信息，其中肌营养不良蛋白和 相关复合物有缺陷（例如DMD、LGMD 2C）或其中肌肉修复受损（例如dysferlin 缺陷），肌肉蛋白质分解的活化大大提高。这个问题的基本假设 有人提出，特异性蛋白酶的靶向抑制可以降低这种升高的周转率， 增加肌肉质量和力量。有许多潜在的靶点，包括细胞内 作为炎症反应的一部分而上调的蛋白酶、钙蛋白酶甚至是 泛素-蛋白体途径这些途径将被特定药物单独或联合抑制 在肌营养不良症小鼠模型中的组合。 随着肌肉萎缩症的进展，肌肉的损失速度加快，因为不活动是强加的。废用 萎缩的基础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组分。这些可能会大大加速肌肉损失， 营养不良的背景使用药物靶向特定的蛋白酶可能会导致废用性萎缩的保留 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价 后肢悬吊。

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.