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层面了解挥发性麻醉药的工作方式。我们有 利用了线虫C.秀丽隐杆线虫的许多优势来识别基因 控制其在挥发性麻醉剂中的行为。我们已经确定一个要点 线粒体电子的第一个复合物的单个亚基中的突变 运输导致秀丽隐杆线虫对所有挥发性麻醉剂非常敏感。该基因GAS-1编码NADH泛氨酮的49KDA亚基 氧化还原酶。新陈代谢的多个方面受到严重影响 突变。此外，自由基损害是其中的重要特征 动物对挥发性麻醉的过敏性。一小群孩子 与与复合物I功能相关的代谢缺陷是 对七氟醚高度敏感。在此提案中，我们将把研究扩展到 检验我们的假设，即新陈代谢减少并增加自由基 构成都在气体1的麻醉性超敏反应中起作用， 这些都可能影响下游突触前靶标。具体目标 本应用程序的内容为：1。比较氟烷对 线粒体缺陷的线虫菌株中的氧化磷酸化， 但是具有不同的麻醉敏感性。这将确定 代谢变化对麻醉灵敏度的贡献。 2。特征 三种蠕虫菌株中的活性氧损害 影响线粒体的突变。我们将确定特定的分子 受麻醉敏感性的活性氧影响。 3。 确定气1对突触结构和功能多个标记的影响 在秀丽隐杆线虫中。突触前蛋白的抗体以及转基因 携带明显突触前蛋白的动物将用于测试效果 在神经元蛋白上的气1，这是突触功能的关键。 线粒体的功能代表了一种新的机制，有助于 整个动物在挥发性麻醉剂中的行为控制。研究 线虫可以导致对挥发性麻醉的分子理解 工作。此外，该建议在 线粒体肌病患者的麻醉反应。