Pathogenic mechanisms that initiate DMD

引发 DMD 的致病机制

• 批准号: 6953247
• 负责人: ROBERT W GRANGE
• 金额: $ 32.35万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953247
• 关键词: biomechanics; calcium flux; disease /disorder etiology; dystrophin; electron spin resonance spectroscopy; fluorescence microscopy; gel electrophoresis; gene mutation; genetically modified animals; immunocytochemistry; laboratory mouse; membrane activity; membrane permeability; muscle contraction; muscle function; muscular dystrophy; myofibrils; protein degradation; protein structure function; sarcolemma; striated muscles; western blottings

DESCRIPTION (provided by applicant): The specific objective of these studies is to discriminate between the potential influences of mechanical perturbations at the sarcolemmal membrane from those of disrupted cross bridge function in the onset of Duchenne's muscular dystrophy (DMD). We will also address the possibility that cytosolic calcium handling is compromised during the early stages of the disease process. DMD is the most common and severe of the muscular dystrophies affecting in widespread fashion, skeletal, smooth and heart muscle. The loss of dystrophin, and additional proteins of the dystrophin-glycoprotein complex from the muscle membrane characterize DMD. This deficiency is thought to render the membrane susceptible to injury, leaky to Ca 2+, disrupted for cell signaling, or a combination of these. Unfortunately, the specific biological mechanisms that initiate DMD are not yet known. It is therefore critical to determine the specific mechanisms responsible for DMD very early in maturation to develop therapeutic approaches to blunt or even eliminate its onset. We will assess skeletal muscles from pups of control, mdx, utrophin -/- (utrn -/-) and mdx:utrn -/- mice (a mouse model of DMD that lacks both dystrophin and its homolog, utrophin) at several ages between 7-28 d. We will test the overarching hypothesis that attenuated dystrophic skeletal muscle function during early maturation is due to disruptions in the contractile apparatus and/or calcium handling rather than due to mechanical instability of the sarcolemma. In Specific Aim 1, we will test the hypothesis that overall muscle force generating capability is decreased independent of membrane damage. In Specific Aim 2 we will determine if the force loss is due to a compromised contractile apparatus. In Specific Aim 3, we will test the hypothesis that the force loss is due to disrupted cytosolic calcium handling. These studies will delineate the contribution of mechanical influences at the membrane from those of disrupted cross bridge function in the onset of DMD, as well as determine the role of calcium handling. These studies will provide valuable insight for the development of therapeutic interventions to prevent the onset of DMD.

描述（由申请人提供）：这些研究的具体目的是区分杜兴氏肌营养不良症（DMD）发作时肌膜膜机械扰动与跨桥功能破坏的潜在影响。我们还将解决在疾病过程的早期阶段细胞质钙处理受到损害的可能性。 DMD 是最常见和最严重的肌营养不良症，广泛影响骨骼肌、平滑肌和心肌。肌营养不良蛋白和肌膜上肌营养不良蛋白-糖蛋白复合物的额外蛋白质的损失是 DMD 的特征。这种缺陷被认为会使膜容易受到损伤、Ca 2+ 渗漏、细胞信号传导中断或这些情况的组合。不幸的是，引发 DMD 的具体生物学机制尚不清楚。因此，在成熟早期确定导致 DMD 的具体机制至关重要，以开发治疗方法来减缓甚至消除其发作。 我们将评估 7-28 天之间多个年龄的对照小鼠、mdx、utropin -/- (utrn -/-) 和 mdx:utrn -/- 小鼠（缺乏肌营养不良蛋白及其同源物 utropin 的 DMD 小鼠模型）的骨骼肌。我们将检验一个总体假设，即早期成熟过程中营养不良性骨骼肌功能的减弱是由于收缩装置和/或钙处理的破坏，而不是由于肌膜的机械不稳定性。在具体目标 1 中，我们将检验以下假设：整体肌肉产生力量的能力下降，而与膜损伤无关。在特定目标 2 中，我们将确定力损失是否是由于收缩装置受损所致。在具体目标 3 中，我们将检验以下假设：力损失是由于细胞质钙处理中断造成的。这些研究将描述 DMD 发作时跨桥功能破坏对膜的机械影响的影响，并确定钙处理的作用。 这些研究将为开发预防 DMD 发病的治疗干预措施提供宝贵的见解。