Basic and Translational Research on General Anesthetics

全身麻醉的基础与转化研究

• 批准号: 10599115
• 负责人: STUART A FORMAN
• 金额: $ 70.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599115
• 关键词: Acceleration; Address; Adopted; Affect; Agonist; Alcohols; Alphaxolone; Anesthetics; Animals; Area; Awareness; Barbiturates; Basic Science; Behavioral; Chemicals; Clinical; Conscious; Drug Interactions; Drug Receptors; Electrophysiology (science); Etomidate; Family; General Anesthesia; General anesthetic drugs; Goals; Grant; International; Intervention; Ion Channel Gating; Kinetics; Knock-in; Knock-out; Knowledge; Larva; Libraries; Ligands; Maps; Mediating; Medical; Membrane; Memory; Mission; Modeling; Molecular; Molecular Target; Motor; Mutation; National Institute of General Medical Sciences; Neural Inhibition; Neurophysiology - biologic function; Nociception; Pharmaceutical Preparations; Physicians; Proteins; Research; Research Support; Research Training; Role; Scientist; Secure; Site; Structure; Synapses; Testing; Time; Toxic effect; Training Programs; Transgenic Organisms; Translational Research; United States National Institutes of Health; Work; Zebrafish; gamma-Aminobutyric Acid; hypnotic; improved; innovation; neurosteroids; pharmacodynamic model; pharmacologic; receptor; response; sedative; tool

Project Summary. General anesthesia, the reversible pharmacologic inhibition of neural functions underlying consciousness, awareness, memory, and nociceptive motor responses, is an essential medical intervention. There is a clear need for new anesthetic drugs with predictable kinetics and reduced toxicity, which will facilitate medical procedural innovation, efficacy, efficiency, and accessibility. I have contributed to these goals using two rigorous and complementary strategies. First, I have rigorously advanced basic science knowledge of molecular anesthetic mechanisms in established targets such as GABAA receptors. This research has revealed unexpectedly specific interactions between different general anesthetic chemotypes (etomidate derivatives, methyl-phenyl allyl barbiturates or MPABs, neurosteroids like alphaxalone, and benzoyl alcohols) and distinct sets of transmembrane inter-subunit sites in typical synaptic GABAA receptors. I also introduced Monod-Wyman-Changeux (MWC) two-state co-agonist models for quantitative analysis of anesthetic effects in these receptors. Second, recognizing that GABAA receptor-specific drugs have proven unsatisfactory as sole clinical general anesthetic agents, I am among the first to adopt zebrafish as an unbiased pharmacodynamic model to discover new hypnotic chemotypes that may act via multiple molecular targets, and to develop transgenic lines to accelerate mechanisms research. The broad long-term objectives of this R35 (MIRA) grant during the next five years and beyond are to further advance our understanding of anesthetic mechanisms at the molecular level, to discover new chemical families with sedative-hypnotic activity, and to create new transgenic zebrafish to test the roles of specific drug-receptor interactions in anesthetic effects. Molecular knowledge areas that will be addressed by this project include, but are not limited to improving the precision of anesthetic site mapping in GABAA receptors, developing MWC models that account for differential agonist versus GABA modulation effects of the distinct site-selective anesthetic chemotypes, probing the subunit arrangement and structures of other important (e.g. extra-synaptic) GABAA receptor isotypes using subsite-specific anesthetics and mutations that selectively affect their actions, and extending these structure-function approaches to other anesthetic-sensitive pentameric ligand-gated ion channels. I will also apply the platform combining zebrafish larvae and real-time video analysis of up to 96 animals at a time to identify new sedative-hypnotic chemotypes in drug libraries and assess a variety of sedative-hypnotic drug interactions. New hypnotic chemotypes will be characterized for effects in a panel of molecular anesthetic targets using electrophysiology and pharmacologic tools. I will also develop new transgenic zebrafish lines with knock-out or knock-in mutations in anesthetic target proteins as models for testing if these targets mediate the behavioral effects of established or discovered sedative-hypnotics.

项目摘要。全身麻醉，可逆的药理学抑制神经功能的神经功能 意识，意识，记忆和伤害感受运动反应是必不可少的医疗干预措施。 显然需要具有可预测动力学和降低毒性的新麻醉药物，这将 促进医疗程序创新，功效，效率和可及性。我为这些目标做出了贡献 使用两种严格和互补的策略。首先，我拥有严格的先进基础科学知识 诸如GABAA受体之类的既定靶标中的分子麻醉机制。这项研究有 揭示了不同一般麻醉化学型之间出乎意料的特异性相互作用（etomaties 衍生物，甲基 - 苯基烯丙基甲贝酸酯或MPABS，含量等神经类固醇和苯甲酰醇） 以及典型的突触GABAA受体中的一组跨膜间跨膜间位点。我也介绍了 单人卫生 - 变换（MWC）两态共同模型，用于定量分析麻醉效应中的麻醉效应 这些受体。其次，认识到GABAA受体特异性药物已被证明不令人满意 临床通用麻醉剂，我是第一个采用斑马鱼作为公正的药效学的人之一 发现可能通过多个分子靶标起作用的新型催眠化学型，并发展 转基因线以加速机制研究。 R35（MIRA）的广泛长期目标 在接下来的五年及以后的授予是进一步提高我们对麻醉的理解 分子水平的机制，发现具有镇静催眠活性的新化学家族， 并创建新的转基因斑马鱼来测试特定药物相互作用在 麻醉作用。该项目将要解决的分子知识领域包括但不是 仅限于提高GABAA受体中麻醉站点映射的精度，开发MWC模型 解释不同位点选择性麻醉的差异激动剂与GABA调制效应 化学型，探测其他重要（例如突触外）GABAA的亚基排列和结构 使用特异性麻醉和突变，有选择地影响其作用的受体同种型，并且 将这些结构功能的方法扩展到其他对麻醉敏感的五聚配配有离子 频道。我还将应用结合斑马鱼幼虫和最多96的实时视频分析的平台 动物一次在药物库中鉴定新的镇静性催眠化学型，并评估各种 镇静性催眠药相互作用。新的催眠化学型将被表征为在一系列面板中的效果 使用电生理学和药理工具的分子麻醉靶标。我也会开发新的 麻醉靶蛋白中具有敲除或敲除突变的转基因斑马鱼线作为模型 测试这些目标是否介导已建立或发现的镇静性催眠器的行为影响。