SPECIFIC MODIFICATION OF SKELETAL MUSCLE RYANODINE RECEPTOR ACTIVITY

该项目将对肌肉疲劳产生影响，这是人口老龄化中的一个公共卫生问题，也会对神经肌肉疾病和肌肉无力产生影响。ryanodine受体（RyR）钙释放通道调节肌细胞内钙浓度的变化，这对呼吸和运动至关重要。RyR表达缺陷导致子宫内或出生时死亡。RyR在许多其他组织中也很重要，其中它单独或与第二种类型的钙通道组合起作用，以调节细胞内钙离子浓度的变化，这对于包括心脏收缩、血管收缩、神经元活动和免疫应答在内的各种过程是必不可少的。尽管它的重要性，很少有人知道在骨骼肌收缩过程中的RyR通道开放的调节或离子运动通过其孔的机制。由于缺乏针对该通道的特异性探针，通常难以定义RyR在完整组织中的特定作用。RyR是治疗药物改变肌肉收缩的一个明显靶点，但由于缺乏特异性和可逆性药物，尚未被如此使用。在神经肌肉疾病中，肌肉性能降低，疲劳迅速。性能可以通过各种药物，如合成代谢类固醇，不幸的是，有额外的不利作用改善。该项目的目的是（a）发现更多关于骨骼肌RyR通道的调节和离子传导途径，（B）鉴定可用作RyR活性特异性探针的化合物，（c）鉴定将来可能为开发RyR作为治疗靶点提供基础的化合物。

The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a second type of calcium channel, to regulate the changes in the concentrations of calcium ions within the cell, which are essential for a variety of processes including cardiac contraction, vascular constriction, neuronal activity and immune responses. Despite its importance, little is known about the regulation of the RyR channel opening during contraction in skeletal muscle or the mechanisms of ion movement through its pore. It is often difficult to define the specific role of RyRs in intact tissues because of the lack of specific probes for the channel. The RyR is an obvious target for therapeutic drugs to modify muscle contraction, but has not been used as such because of the lack of specific and reversible drugs. Muscle performance is reduced, and fatigue is rapid, in neuromuscular disease. Performance can be improved by variety of drugs like anabolic steroids which unfortunately have additional adverse actions. The aims of the project are (a) to discover more about the regulation of, and ion conduction pathway through, the skeletal muscle RyR channel, (b) to identify compounds that can be used as specific probes for RyR activity and (c) to identify compounds that might in the future provide the basis for development of the RyR as a therapeutic target.