SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热中的骨骼肌损伤

• 批准号: 3271901
• 负责人: THOMAS E NELSON
• 金额: $ 12.89万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3271901
• 关键词: anesthesia complication; atomic absorption spectrometry; biopsy; caffeine; calcium channel; drug adverse effect; drug metabolism; electrochemistry; gene expression; genetic disorder; halothane; human tissue; laboratory rabbit; malignant hyperthermia; membrane permeability; muscle cramp; muscle disorder diagnosis; muscle function; muscle metabolism; muscle pharmacology; sarcoplasmic reticulum; striated muscles; swine

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.

恶性高热是一种危及生命的高代谢综合征 当有遗传倾向的个体暴露在某些 麻醉剂 虽然这种情况很少发生，但一个组织的几个成员 个别家庭可能受到影响， 易受影响的人是有问题的，有时最多拒绝 医疗中心。 这是基于缺乏理解的究竟如何 疾病是遗传的，是什么引发了综合征，以及缺乏一个简单的， 非侵入性诊断测试。 该提案包含实验协议 旨在拓宽我们对该疾病病因的了解，并且 探索新的、侵入性较小的诊断测试， 大多数医疗中心 我们的MH诊断中心执行约75 每年进行诊断试验，我们还维持MH猪动物模型。 根据对MH人和猪的几项研究，已知异常 发生在骨骼肌中。 我们最近发现了一个缺陷， 肌浆网（SR）膜中的通道，调节 MH猪肌肉收缩和舒张的Ca 2+浓度。 我们 初步研究表明，这种钙通道也可能是异常的， 我们的实验就是为了测试这种 假说. 主要目的是从HM和正常人中分离 骨骼肌SR膜组分对于生物化学和 药理学特性，然后比较这些功能之间 从不同的MH诊断组获得的膜。 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，猪的育种实验 计划为我们提供更多关于这些缺陷是如何遗传的信息， 以及如何将这些信息应用于人类MH。 我们参与了 具有独特专业知识的合作者，帮助探索精确的生物化学和 SR膜的生物物理性质，并研究底物 在MH易感个体中循环。 更简单的无创诊断 对血细胞和骨骼肌功能的测试旨在 探索用于MH的微创诊断测试。 所获得的信息将为了解 发病机制，形成诊断基础，并为预防提供理论依据 和/或治疗全身麻醉期间的恶性高热。