Photoactivatable ligands for nicotinic optopharmacology

用于烟碱光药理学的光激活配体

• 批准号: 9751827
• 负责人: Ryan Michael Drenan
• 金额: $ 20.61万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751827
• 关键词: Address; Axon; Basic Science; Behavioral; Biological; Biology; Brain; CRISPR/Cas technology; Catalogs; Cells; Cessation of life; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Data Set; Dendrites; Development; Effectiveness; Electrophysiology (science); Fostering; Glutamates; Goals; Health; Hypertension; Image; Individual; Knowledge; Laser Scanning Microscopy; Lasers; Lateral; Lead; Ligands; Light; Lighting; Location; Malignant neoplasm of lung; Maps; Measures; Mediating; Methods; Modeling; Molecular; Neurons; Neurosciences; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Optical Methods; Optics; Pharmacotherapy; Phase; Physiologic pulse; Presynaptic Terminals; Process; Protocols documentation; Pulmonary Emphysema; Relapse; Research; Resolution; Rewards; Self Administration; Site; Slice; Spottings; System; Techniques; Time; United States; Ventral Tegmental Area; Visible Radiation; Work; addiction; cell type; cholinergic; conditioning; design; dopaminergic neuron; experimental study; feeding; improved; innovation; neuronal cell body; neurotransmission; nicotine exposure; nicotine seeking behavior; nicotine use; novel; patch clamp; preference; quantum; receptor; receptor function; research study; response; smoking cessation; tobacco products; tool; two-photon; ultraviolet

PROJECT SUMMARY Chronic exposure to nicotine in tobacco products results in numerous health consequences (lung cancer, emphysema, hypertension, etc.) and accounts for over 6 million deaths per year. Relapse rates are high among those who attempt to quit smoking, and pharmacotherapies that seek to foster smoking cessation have moderate effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine dependence. Development of such strategies requires a more detailed understanding of the biological mechanisms leading to nicotine addiction. An essential goal related to mechanistic studies on nAChRs is gaining a better understanding of the location and activity of nAChRs in discrete sites within individual nerve cells. Although some basic research studies have begun to describe nAChR subcellular distribution, there is currently no plausible way to functionally interrogate nAChRs at the subcellular level. This means we are currently unable to determine whether the important nicotine-mediated functional alterations in nAChRs occur in dendrites, axons, presynaptic terminals, or in neuronal somata. Answering this key question is absolutely required for the field to fully understand the molecular and cellular basis for nicotine dependence. Here, we propose a R21/R33 phased innovation project that directly addresses these critical gaps in our ability to study native nAChRs. The R21 phase will develop and characterize a photoactivatable nicotine (PA-Nic) compound for use in nicotine “uncaging” experiments. R21 Aim 1 focusses on identification of 1 or more suitable compounds using ultraviolet/visible light optical methods, while Aim 2 will characterize promising compounds using 2-photon uncaging techniques, which offer enhanced spatial resolution. In the R33 phase, we propose to employ these innovative compounds and optical methods in discovery experiments designed to uncover new details about nAChR function. R33 Aim 1 will involve functional mapping of nAChRs on key cell types involved in nicotine dependence. R33 Aim 2 will probe how these receptors enable nicotine to participate in circuit-level modulation of neurotransmission in brain's reward system. This project represents a substantial technical advance for the cholinergic biology field, as it will not only produce new tools for widespread use, but will utilize those tools to uncover new mechanistic details about nicotine dependence.

项目概要 长期接触烟草制品中的尼古丁会导致多种健康后果（肺癌、 肺气肿、高血压等）每年造成超过 600 万人死亡，其中复发率很高。 那些试图戒烟的人以及旨在促进戒烟的药物疗法 因此，对治疗尼古丁的更有效策略的需求尚未得到满足。 制定此类策略需要对生物学有更详细的了解。 导致尼古丁成瘾的机制 与 nAChR 机制研究相关的一个基本目标是 更好地了解个体神经内离散部位中 nAChR 的位置和活性 尽管一些基础研究已经开始描述 nAChR 的亚细胞分布，但仍存在一些问题。 目前还没有在亚细胞水平上对 nAChR 进行功能性研究的合理方法，这意味着我们还没有做到这一点。 目前无法确定尼古丁介导的 nAChR 功能是否发生重要改变 发生在树突、轴突、突触前末梢或神经元体中。回答这个关键问题是。 该领域绝对需要充分了解尼古丁依赖的分子和细胞基础。 在这里，我们提出了一个 R21/R33 分阶段创新项目，直接解决我们能力中的这些关键差距 研究天然 nAChR 相将开发并表征光活化尼古丁 (PA-Nic)。 用于尼古丁“解禁”实验的化合物 R21 目标 1 侧重于识别 1 个或多个。 使用紫外/可见光光学方法的合适化合物，而 Aim 2 将具有前景 我们使用 2 光子解笼技术来合成化合物，该技术可提供增强的 R33 相空间分辨率。 提议在发现实验中采用这些创新化合物和光学方法，旨在 揭示有关 nAChR 功能的新细节 R33 目标 1 将涉及关键细胞上 nAChR 的功能映射。 R33 Aim 2 将探究这些受体如何使尼古丁参与其中。 该项目代表了大脑奖励系统中神经传递的电路级调节。 胆碱能生物学领域的技术进步，因为它不仅会产生广泛使用的新工具，而且 将利用这些工具来揭示有关尼古丁依赖的新机制细节。