SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热(MH)是一种遗传性疾病，存在于人和多种动物中 易患上危及生命的高代谢综合症的物种。 急性起病的MH综合征是由某些意外引发的 麻醉剂。主要的缺陷发生在骨骼肌和 本项目中描述的实验主要关注的是 患者的遗传缺陷及其临床表型表达， 活体骨骼肌的收缩反应、钙摄取和 离体膜囊泡和单个蛋白质分子的释放 起钙通道作用的。这些研究是基于一口井 建立假设认为MH是由麻醉剂诱导的损失引起的 肌浆调节(钙离子)。一种可能的致病单一氨基酸 MH猪肌肉钙释放通道中的取代提供 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。还研究了 是一种带有未知突变的遗传犬MH模型 嗯，猪。以同样的方式研究的MH犬模型将提供新的， 因为猪的突变发生在不到5%的 嗯，人类家庭。动物模型的临床表型由它们的 对麻醉挑战的反应和体外通过肌挛缩 对咖啡因、氟烷和兰尼丁敏感。接受MH手术的患者 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。它们之间的异同之处 肌挛缩反应将通过对钙的研究来探索 分离的肌浆网膜泡和肌浆网膜泡的调节 单兰尼定受体(RyR)钙释放通道分析 一种平面类脂双层。RyR钙通道将在#年进行研究 生物化学和药理学细节提供了联系的基础 结构和功能以及突变对这种关系的影响。 这些信息将为预测两国关系提供基础 特定突变与麻醉剂诱导的易感性之间的关系 恶性高热。这一战略将是评估 新发现的这种主要钙离子突变的临床意义 释放通道。

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.