Pathogenic mechanisms that initiate DMD

描述(申请人提供)：这些研究的具体目标是区分肌膜机械干扰和横桥功能障碍在Duchenne肌营养不良(DMD)发病中的潜在影响。我们还将讨论在疾病过程的早期阶段细胞内钙处理受到影响的可能性。DMD是肌肉营养不良中最常见和最严重的一种，广泛影响骨骼肌、平滑肌和心肌。DMD的特征是肌营养不良蛋白的丢失，以及肌肉膜上的肌营养不良蛋白-糖蛋白复合体的额外蛋白。这种缺陷被认为使膜容易受到伤害，对钙离子泄漏，扰乱细胞信号，或这些因素的组合。不幸的是，引发DMD的具体生物学机制尚不清楚。因此，在DMD成熟早期就确定其具体的致病机制，以开发治疗方法来钝化甚至消除其发病是至关重要的。 我们将在7-28天期间评估几只年龄在7-28天的对照、MDX、UTUN-/-(UTUN-/-)和MDX：UTUN-/-DMD(DMD的小鼠模型，缺乏Dstrophin及其同系物，utroin)小鼠的骨骼肌。我们将检验最重要的假说，即早期成熟期间营养不良的骨骼肌功能减弱是由于收缩装置和/或钙处理的中断，而不是由于肌膜的机械不稳定。在特定的目标1中，我们将检验这样的假设，即整体肌肉力量产生能力的降低与膜损伤无关。在特定的目标2中，我们将确定力量损失是否由受损的收缩装置引起。在特定的目标3中，我们将测试这一假设，即力损失是由于细胞内钙处理中断所致。这些研究将阐明在DMD发病过程中，跨桥功能受损对细胞膜机械影响的贡献，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.