Ketamine-Class Antidepressants in Vesicles

囊泡中的氯胺酮类抗抑郁药

• 批准号: 9809829
• 负责人: Henry A. Lester
• 金额: $ 24.68万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809829
• 关键词: Action Potentials; Adverse effects; Anesthetics; Antidepressive Agents; Biophysics; Biosensor; Brain; Calibration; Cell membrane; Cells; Cytoplasm; Data; Dependovirus; Development; Dose; Drug Kinetics; Drug effect disorder; Electrophysiology (science); Endoplasmic Reticulum; Endosomes; Engineering; Event; Family; Fluorescence; Future; Goals; Golgi Apparatus; Hour; Image; Invaded; Ketamine; Knowledge; Ligands; Lysosomes; Mammalian Cell; Measures; Mediating; Membrane; Mental Depression; Molecular Target; Mus; Neurotransmitters; Norepinephrine; Organelles; Pharmaceutical Preparations; Pharmacology; Presynaptic Terminals; Procedures; Process; Property; Reporter; Research; Research Personnel; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Slice; Sum; Synapses; Synaptic Cleft; Synaptic Vesicles; Testing; Time; Vesicle; Work; World Health Organization; antidepressant effect; base; burden of illness; depressive symptoms; disability; drug development; experimental study; inhibitor/antagonist; innovation; neurotransmitter release; next generation; novel; phrases; predictive test; programs; reduce symptoms; response; side effect; spatiotemporal; success; tool

The project studies ketamine, its metabolites, and related drugs [Ketamine-Class Antidepressant Drugs (KCADs), our term]. Sub-anesthetic doses of ketamine produce antidepressant effects in just a few hours (2 h) via unknown mechanism(s). However, higher doses have adverse effects. Understanding the mechanism mediating KCAD antidepressant activity is an important step in the process of drug development. This research program has the goal to fundamentally change our understanding of how this rapid antidepressant mechanism works and holds promise for development of more robust and safer treatments. The molecular target(s) of KCAD action are not known. In the absence of such knowledge, one should investigate possible actions in the compartments where KCADs are most concentrated. We test the hypothesis that the effects of KCADs in the brain are mediated, in least in part, by the accumulation of KCADs in various subcellular compartments (organelles), including synaptic vesicles. Aim 1 develops a family of next-generation genetically encoded “Intensity-based Ketamine-Sensing Fluorescent Reporters” (iKetSnFRs) for KCADs. These will dynamically image and quantify the presence of KCADs at sub-cellular levels. Aim 1 measures the time course of KCAD entry and exit from various organelles after the drugs appear or disappear near cells. Aim 2 tests the hypothesis that the antidepressant mechanism of KCADs involves accumulation in the lumen of acidic vesicles, especially in synaptic vesicles, followed by synaptic stimulation-induced release of KCAD from presynaptic terminals. Aim 3 detects KCAD-induced neurotransmitter release from presynaptic terminals, employing next generation genetically encoded biosensors for various neurotransmitters. The experiments also include electrophysiological studies of membrane and synaptic properties. The data from Aims 1, 2 and 3 will not in themselves develop a new ~2 h antidepressant drug. But the data from the proposed experiments can help to understand how KCADs exert their effects. The data will also guide the development of related molecules with fewer potential side effects as new fast-acting therapies for depression.

该项目研究氯胺酮、其代谢物和相关药物[氯胺酮类抗抑郁药 药物（KCAD），我们的术语]。亚麻醉剂量的氯胺酮可产生抗抑郁作用 通过未知机制仅需几个小时（2 小时）。然而，较高剂量会产生副作用。 了解 KCAD 抗抑郁活性的介导机制是实现这一目标的重要一步 药物开发过程。该研究计划的目标是从根本上改变我们的 了解这种快速抗抑郁机制如何发挥作用并有望实现 开发更强大、更安全的治疗方法。 KCAD 作用的分子靶标尚不清楚。在缺乏这些知识的情况下，一个人 应调查 KCAD 最集中的隔间中可能采取的行动。 我们检验了这样的假设：KCAD 在大脑中的影响至少部分是由 KCAD 在各种亚细胞区室（细胞器）中积累，包括突触 囊泡。 Aim 1 为 KCAD 开发了一系列下一代基因编码的“基于强度的氯胺酮感应荧光报告基因”(iKetSnFR)。这些将动态成像并 量化 KCAD 在亚细胞水平的存在。目标 1 测量 KCAD 的时间进程 药物在细胞附近出现或消失后进入和退出各种细胞器。目标 2 测试 KCAD 的抗抑郁机制涉及管腔内积累的假设 酸性囊泡，特别是突触囊泡，然后是突触刺激诱导的释放 来自突触前终端的 KCAD。目标 3 检测 KCAD 诱导的神经递质释放 突触前末梢，采用下一代基因编码生物传感器进行各种 神经递质。实验还包括膜的电生理学研究 突触特性。 目标 1、2 和 3 的数据本身不会开发出新的约 2 小时抗抑郁药物。 但所提出的实验数据可以帮助理解 KCAD 如何发挥其作用 影响。该数据还将指导潜力面较少的相关分子的开发 作为治疗抑郁症的新的速效疗法。