Mitochondrial Effects on Sensitivity to Anesthetics

线粒体对麻醉药敏感性的影响

• 批准号: 6436881
• 负责人: Margaret Mary Sedensky
• 金额: $ 36.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436881
• 关键词: Caenorhabditis elegans; alternatives to animals in research; anesthetics; drug hypersensitivity; drug metabolism; free radical oxygen; gene mutation; halothane; inhalation anesthesia; mitochondria; neurophysiology; oxidative phosphorylation; pharmacogenetics; pharmacokinetics; stereoisomer; synapses

DESCRIPTION (provided by applicant): The long-term goal of this laboratory is to understand at the molecular level how the volatile anesthetics work. We have exploited the many advantages of the nematode C. elegans to identify genes that control its behavior in volatile anesthetics. We have determined that a point mutation in a single subunit of the first complex of mitochondrial electron transport causes C. elegans to be profoundly hypersensitive to all volatile anesthetics. This gene, gas-1, encodes the 49Kda subunit of NADH ubiquinone oxidoreductase. Multiple aspects of metabolism are severely affected by this mutation. In addition, free radical damage is a significant feature of this animal's hypersensitivity to volatile anesthetics. A small group of children with metabolic defects that are related to the function of Complex I are hypersensitive to sevoflurane. In this proposal we will extend our studies to test our hypothesis that decreased metabolism and increased free radical formation both play a role in the anesthetic hypersensitivity of gas-1, and the either of these may affect downstream, presynaptic targets. The specific aims of the present application are to: 1. Compare the effect of halothane on oxidative phosphorylation in nematode strains with known mitochondrial defects, but with different anesthetic sensitivities. This will determine the contribution of metabolic changes on anesthetic sensitivity. 2. Characterize the damage from reactive oxygen species in three strains of worms with mutations that affect mitochondria. We will identify specific molecules affected by reactive oxygen species that affect anesthetic sensitivity. 3. Determine gas-1's effect on multiple markers of synaptic structure and function in C. elegans. Antibodies to presynaptic proteins, as well as transgenic animals carrying marked presynaptic proteins, will be used to test the effects of gas-1 on neuronal proteins that are key to synaptic function. The function of mitochondria represents a novel mechanism that contributes to the control of behavior of a whole animal in volatile anesthetics. Study of the nematode can lead to a molecular understanding of how volatile anesthetics work. In addition, this proposal has a clear clinical correlate in the anesthetic response of patients with mitochondrial myopathies.

描述（由申请人提供）：本实验室的长期目标是 在分子水平上了解挥发性麻醉剂是如何工作的。我们有 利用了线虫C.来识别那些 控制其在挥发性麻醉剂中的行为。我们已经确定， 线粒体电子复合体第一复合体单亚基突变 运输原因C.对所有挥发性物质都极度敏感 麻醉剂该基因，gas-1，编码NADH泛醌的49 Kda亚基 氧化还原酶。新陈代谢的多个方面都受到严重影响 突变此外，自由基损伤是这一显著特征 动物对挥发性麻醉剂的超敏反应。一小部分孩子 与复合体I功能相关的代谢缺陷是 对七氟烷过敏在这项建议中，我们将把研究扩展到 测试我们的假设，降低新陈代谢和增加自由基 形成都发挥作用的麻醉过敏性气体-1，和 这两种情况中的任何一种都可能影响下游的突触前靶点。具体目标 本申请的目的在于：1.比较氟烷对 在具有已知线粒体缺陷的线虫菌株中的氧化磷酸化， 但麻醉敏感性不同。这将决定 代谢变化对麻醉剂敏感性的影响。2.表征 活性氧对三株蠕虫的损伤作用 影响线粒体的突变我们将识别特定的分子 受到影响麻醉剂敏感性的活性氧的影响。3. 确定GAS-1对突触结构和功能的多个标志物的影响 in C.优雅的突触前蛋白的抗体，以及转基因 携带有标记的突触前蛋白的动物将被用来测试这种效应 神经元蛋白质上的气体-1是突触功能的关键。 线粒体的功能代表了一种新的机制，有助于 用挥发性麻醉剂控制整个动物的行为。研究 线虫可以帮助我们从分子水平上理解挥发性麻醉剂 工作此外，该建议在以下方面具有明确的临床相关性： 线粒体肌病患者的麻醉反应。