SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热（malignant hyperthermia，MH）是一种遗传性疾病 易患危及生命的高代谢综合征的物种。 急性发作的MH综合征是由某些 麻醉剂主要缺陷发生在骨骼肌中， 在这个项目中描述的实验集中在 患者的遗传缺陷及其临床表型表达， 活检骨骼肌中的挛缩反应、钙摄取和 通过分离的膜囊泡和单个蛋白质分子释放 作为钙离子通道。这些研究是基于一口井 建立了MH是由麻醉剂引起的损失引起的假设 肌浆（Ca 2+）的调节。一种可能的致病的单一氨基酸 在MH猪肌肉的钙释放通道中的取代提供了 用于表征该突变的表型表达的模型， 动物、组织、膜和蛋白质水平的组织。 还研究 是一种遗传性犬MH模型，其具有不同于 我的猪。以同样方式研究的MH犬模型将提供新的， 因为猪的突变发生在不到5%的 人类家庭。动物模型的表型临床上通过其 对麻醉剂激发的反应和体外挛缩 对咖啡因、氟烷和兰尼碱敏感。接受MH的患者 诊断性肌肉活检将为平行研究提供肌肉 那些在动物模型中。 的相似性和不同点 挛缩反应将通过研究钙来探索 通过分离的肌浆网膜囊泡和 分析单个Ryanodine受体（RYR）钙释放通道在 平面脂质双层。RYR钙通道将在 生物化学和药理学的细节，以提供基础， 结构和功能以及突变对这种关系的影响。 这些信息将为预测这种关系提供基础 特定的突变和麻醉诱导的 恶性高热 这一战略对于评估 新发现的这一主要钙离子突变的临床相关性 释放频道

Malignant hyperthermia (MH) is a genetic disease in man and various animal species which predisposes to a life-threatening hypermetabolic syndrome. The acute onset MH syndrome is triggered unexpectedly by certain anesthetic agents. The primary defect occurs in skeletal muscle and experiments described in this project focus on the relationships between genetic defect and its phenotypic expression clinically in the patient, contracture response in biopsied skeletal muscle, calcium uptake and release by isolated membranes vesicles and a single protein molecule functioning as a calcium channel. These studies are based on a well founded hypothesis that MH is caused by anesthetic agent-induced loss in regulation of myoplasmic (Ca2+). A probable causal single amino acid substitution in the calcium release channel of MH pig muscle provides the model for characterizing phenotypic expression of this mutation at the animal, tissue, membrane and protein levels of organization. Also studied is a genetic canine MH model with an unknown mutation different from the MH pig. The MH canine model, studied in the same manner, will provide new, informative knowledge because the pig mutation occurs in less than 5% of MH human families. Animal models are phenotyped clinically by their response to anesthetic challenge and by in vitro by contracture sensitivity to caffeine, halothane, and ryanodine. Patients undergoing MH diagnostic muscle biopsies will provide muscle for studies parallel to those in the animal models. Similarities and dissimilarities among the contracture responses will be explored by investigation of calcium regulation by isolated sarcoplasmic reticulum membrane vesicles and by analysis of the single ryanodine receptor (RYR) calcium release channel in a planar lipid bilayer. The RYR calcium channel will be studied in biochemical and pharmacological detail to provide a basis for linking structure and function and the impact of mutations on this relationship. Such information will provide a basis for predicting the relationship between a specific mutation and susceptibility to anesthetic-induced malignant hyperthermia. This strategy will be essential for assessing the clinical relevance of newly discovered mutations in this major calcium release channel.