Pathogenic mechanisms that initiate DMD

描述（由申请方提供）：这些研究的具体目的是区分肌膜机械扰动的潜在影响与杜氏肌营养不良症（DMD）发作时横桥功能破坏的潜在影响。我们还将讨论在疾病过程的早期阶段细胞溶质钙处理受到损害的可能性。DMD是最常见和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营养不良蛋白-糖蛋白复合物从肌膜的额外蛋白质的损失表征DMD。这种缺陷被认为使细胞膜易受损伤，对Ca 2+渗漏，细胞信号传导中断，或这些的组合。不幸的是，引发DMD的具体生物学机制尚不清楚。因此，至关重要的是要确定负责DMD的特定机制非常早的成熟，以开发治疗方法，以钝，甚至消除其发作。 我们将评估来自对照、mdx、utrophin -/-（utrn -/-）和mdx：utrn -/-小鼠（缺乏肌营养不良蛋白及其同源物utrophin的DMD小鼠模型）的7-28日龄的幼仔的骨骼肌。我们将测试的首要假设，衰减营养不良的骨骼肌功能在早期成熟是由于中断的收缩装置和/或钙处理，而不是由于机械不稳定的肌膜。在具体目标1中，我们将检验以下假设：整体肌肉力量产生能力降低，与膜损伤无关。在具体目标2中，我们将确定力损失是否是由于收缩装置受损所致。在特定目标3中，我们将检验力损失是由于胞质钙处理中断所致的假设。这些研究将描述DMD发病中跨桥功能破坏对膜机械影响的贡献，并确定钙处理的作用。 这些研究将为预防DMD发作的治疗干预措施的发展提供有价值的见解。

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.