SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热(MH)是一种危及生命的高代谢综合征 当遗传倾向的个体暴露于某些特定的 麻醉剂。虽然很少发生，但有几个成员 个别家庭可能会受到影响，这些家庭的医疗管理 易受影响的人是有问题的，有时最多被拒绝 医疗中心。这是基于对如何准确地理解 疾病是遗传的，是什么触发了综合征，并且缺乏简单的， 无创诊断试验。该提案包含实验性协议 旨在扩大我们对疾病病因的理解，以及 探索新的、侵入性较小的诊断测试，可应用于 大多数医疗中心。我们的MH诊断中心执行大约75 每年进行诊断性测试，我们还维持MH猪的动物模型。 根据对MH人和猪的几项研究，异常是已知的 发生在骨骼肌中。我们最近发现了钙离子释放的缺陷 肌浆网(SR)膜上调节细胞周期变化的通道 钙离子浓度对MH猪肌肉收缩和松弛的影响。我们的 初步研究表明，这一钙通道可能也存在异常。 人类肌肉和我们的实验就是为了测试这样一种 假设。主要目标是从HM和正常人中分离出来 骨骼肌肌质网膜组分，其生化和 药理特性，然后比较这些功能在 膜取自不同的MH诊断组。其他实验 旨在研究这些SR膜的组成以及 它们的生物物理特性。此外，在猪身上进行的育种实验也是 计划给我们更多关于这些缺陷是如何遗传的信息 以及如何将这一信息应用于人类MH。我们已经参与了 具有独特专业知识的合作者，帮助探索精确的生化和 SR膜的生物物理性质及其底物的研究 在MH易感人群中骑自行车。更简单的非侵入性诊断 血细胞和骨骼肌功能测试旨在 探索对MH进行侵入性较小的诊断测试。 所获得的信息将为理解 发病机制，形成诊断基础，并为预防提供理论基础 和/或全身麻醉期间恶性高热的治疗。

Malignant hyperthermia (MH) is a life-threatening hypermetabolic syndrome that occurs when genetically predisposed individuals are exposed to certain anesthetic agents. Although of rare occurrence, several members of an individual family may be affected and medical management of these susceptible individuals is problematic and sometimes refused at most medical centers. This is based on lack of understanding of exactly how the disease is inherited, what triggers the syndrome, and absence of a simple, noninvasive diagnostic test. This proposal contains experimental protocols designed to broaden our understanding of the etiology of the disease, and to explore for new, less invasive diagnostic tests that can be applied at most medical centers. Our MH diagnostic center performs about 75 diagnostic tests per year and we also maintain a MH porcine animal model. Based on several studies in MH man and swine, abnormalities are known to occur in skeletal muscle. We recently discovered a defect in Ca2+ release channels in sarcoplasmic reticulum (SR) membranes that regulate changes in Ca2+ concentration for contraction and relaxation of MH pig muscle. Our preliminary studies suggest that this Ca2+ channel may also be abnormal in MH human muscle and our experiments are designed to test such a hypothesis. The primary goal is to isolate from HM and normal human skeletal muscle SR membrane fractions that are uniform for biochemical and pharmacologic properties and then to compare these functions among membranes obtained from different MH diagnostic groups. Other experiments are designed to study the composition of these SR membranes as well as their biophysical properties. Also, breeding experiments in pigs are planned to give us more information on how these defects are genetically determined and how to apply this information to human MH. We have involved collaborators with unique expertise to help explore precise biochemical and biophysical properties of the SR membranes and to investigate substrate cycling in the MH susceptible individuals. Simpler, noninvasive diagnostic tests on blood cells and on skeletal muscle function are designed to explore for less invasive diagnostic tests for MH. The information obtained will provide a basis for understanding the pathogenesis, form a diagnostic base, and give rationale for prevention and/or treatment of malignant hyperthermia during general anesthesia.