Mitochondrial Effects on Sensitivity to Anesthetics

线粒体对麻醉药敏感性的影响

• 批准号: 6692654
• 负责人: Margaret Mary Sedensky
• 金额: $ 39.8万
• 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/6692654
• 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）：该实验室的长期目标是在分子水平上了解挥发性麻醉剂的工作原理。我们有 利用线虫秀丽隐杆线虫的许多优势来鉴定基因 控制其在挥发性麻醉剂中的行为。我们确定了一个点 线粒体电子第一复合体单个亚基突变 运输导致线虫对所有挥发性麻醉剂极度过敏。该基因，gas-1，编码 NADH 泛醌的 49Kda 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，自由基损伤也是其一个显着特征。 动物对挥发性麻醉剂过敏。一小群孩子 与复合物 I 功能相关的代谢缺陷是 对七氟醚过敏。在本提案中，我们将把我们的研究扩展到 检验我们的假设，即新陈代谢降低和自由基增加 形成都在gas-1的麻醉超敏性中发挥作用，并且 其中任何一个都可能影响下游的突触前目标。具体目标 本申请的目的是： 1.比较氟烷对 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 代谢变化对麻醉敏感性的贡献。 2. 表征 活性氧对三种蠕虫菌株的损害 影响线粒体的突变。我们将识别特定分子 受影响麻醉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 在线虫中。突触前蛋白抗体以及转基因抗体 携带标记突触前蛋白的动物将用于测试效果 神经元蛋白上的gas-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 在挥发性麻醉剂中控制整个动物的行为。研究的 线虫可以从分子角度理解挥发性麻醉剂的作用 工作。此外，该提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。