Protease Inhibition as Possible therapy for Muscular Dystrophy
Protease Inhibition as Possible therapy for Muscular Dystrophy
批准号:
7648211
负责人:
H Lee Sweeney
金额:
$47.05万
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-06-01 至 2010-05-31
关键词:
AddressApoptosisApoptoticAtrophicAttenuatedCalciumCalpainClassComplexCoupledDYSF geneDefectDisuse AtrophyDrug usageDystrophinEndopeptidasesExtracellular MatrixGoalsGrowthHindlimb SuspensionInflammatory ResponseInsulin-Like Growth Factor IInterventionKnockout MiceLeadLeupeptinsMediatingMusMuscleMuscle ProteinsMuscle functionMuscular AtrophyMuscular DystrophiesNumbersPathway interactionsPeptide HydrolasesPharmaceutical PreparationsPredispositionProcessProtease InhibitorProteasome InhibitorProtein BiosynthesisProteinsRateSarcoglycansSerine ProteaseSignal PathwaySignal TransductionSkeletal MuscleUbiquitinUpper armbaseexperienceextracellularfallsinhibitor/antagonistleupeptinmouse modelmulticatalytic endopeptidase complexmuscular dystrophy mouse modelmyostatinpreventprotein degradationrepairedsatellite celltherapeutic targetubiquitin ligase
中文摘要
蛋白水解酶抑制可作为肌营养不良的可能治疗方法
这个项目的主要目标是减缓骨骼肌质量和功能的损失
营养不良过程的后果。在肌营养不良症中,肌营养不良蛋白和
相关复合体有缺陷(如DMD、LGMD2C)或肌肉修复受损(如干扰素障碍)
缺陷),肌肉蛋白质分解的活性大大提高。这其中的基本假设是
建议是,有针对性地抑制特定的蛋白酶可以减少这种升高的周转,导致
增加肌肉质量和力量。有许多潜在的目标,包括细胞内
作为炎症反应的一部分而上调的蛋白水解酶,钙蛋白酶,甚至是
泛素-蛋白酶体途径。这些通路将被特定的药物单独和在
联合应用于肌营养不良症小鼠模型。
随着肌肉营养不良的发展,肌肉丧失的速度会随着不活动的增加而加快。停用
萎缩的根本原因有三个:蛋白质降解增加,蛋白质减少
合成和一种短暂的细胞凋亡成分。这些可能会极大地加速肌肉的损失
营养不良背景。使用药物靶向特定的蛋白水解酶可能会导致废用性萎缩。
以及与营养不良本身相关的肌肉损失。这将在营养不良的小鼠身上进行评估
后肢悬吊。
英文摘要
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.
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依托单位:
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批准号:10459579
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依托单位:
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依托单位:
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