Ion Channel Pharmacology for Pain and Epilepsy

疼痛和癫痫的离子通道药理学

• 批准号: 10615776
• 负责人: BRUCE P BEAN
• 金额: $ 108.71万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2030-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615776
• 关键词: Accidents; Action Potentials; Ataxia; Behavior; Calcium Channel; Clinical; Complex; Dependence; Disease; Drug Targeting; Elements; Epilepsy; Foundations; Functional disorder; Goals; Grant; Hippocampus; Individual; Ion Channel; Knowledge; Laboratories; Membrane Potentials; Motor Neurons; Nervous System Physiology; Neurons; Nociceptors; Pain; Pattern; Peptides; Pharmacology; Population; Potassium Channel; Research; Role; Shapes; Sodium Channel; Spinal Cord; Toxin; Work; cell type; design; differential expression; drug action; experience; hippocampal pyramidal neuron; interest; neuronal patterning; novel; pharmacologic; preservation; rational design; small molecule; targeted agent; voltage

Project Summary/ Abstract The proposed work will integrate two long-standing lines of research in the laboratory. One is to understand is to understand how the many types of ion channels present in a single neuron work together to regulate its firing pattern. In earlier grant periods, we focused on the individual gating behavior and functional roles of various kinds of calcium channels, sodium channels, and potassium channels in different kinds of mammalian neurons. More recently, we have tried to understand how the currents through the many kinds of channels in a given neuronal type interact, often in surprising ways, to control the firing pattern of the neuron. In a second line of research, we have characterized a variety of pharmacological agents that are targeted to voltage-dependent channels. Much of this work originally focused on finding peptide toxins and small molecules useful for separating components of current from specific channel types. Our goal now is to use our expanding knowledge about the differences in ion channel make-up of different kinds of neurons to rationally design novel compounds that can inhibit (or enhance) activity of specific kinds of neurons. Hypothesizing that it is no accident that many clinically- effective drugs act on multiple ion channels, we will attempt to design single compounds deliberately designed to inhibit or enhance specific combinations of voltage-dependent sodium, potassium, and calcium channels to differentially depress (or enhance) firing of specific neuronal types of interest, including primary nociceptors, hippocampal and cortical pyramidal neurons, various populations of cortical and hippocampal GABAergic neurons, and spinal cord motor neurons, in ways designed to have clinically beneficial effects. A key element of our approach is realizing that almost all small-molecule compounds targeted to voltage-dependent channels interact differentially with different gating states of the channels, resulting in complex dependence on voltage waveforms. Thus, differential inhibition of different neuronal types can be based on their different resting potentials, action potential shapes, and firing patterns as well as presence or absence of particular channel types being targeted. Our previous experience with a range of cell types, channel types, and channel-targeted drugs will provide a strong foundation for this effort.

项目摘要/摘要 拟议的工作将在实验室中整合两种长期的研究线。一个是 了解是了解单个神经元中的许多类型的离子通道如何 共同努力以调节其射击方式。在较早的赠款期间，我们专注于个人 门控行为和各种钙通道，钠通道和功能作用 钾通道中的不同种类的哺乳动物神经元。最近，我们试图 了解给定神经元中多种频道的电流如何 通常以令人惊讶的方式相互作用，以控制神经元的触发模式。第二行 研究，我们表征了各种针对的药理学剂 电压依赖性通道。这项工作的大部分最初都集中在寻找肽毒素和 小分子可用于将电流的组分与特定通道类型分开。我们的 现在的目标是利用我们对离子渠道构成差异的扩展知识 不同种类的神经元以合理设计可以抑制（或增强）的新型化合物 特定类型的神经元的活性。假设在许多临床上，这绝非偶然 有效药物在多个离子通道上作用，我们将尝试设计单个化合物 故意设计以抑制或增强电压依赖性钠的特定组合， 钾和钙通道差异降低（或增强）特定神经元的发射 感兴趣的类型，包括主要伤害感受器，海马和皮质金字塔神经元， 各种皮质和海马GABA能神经元以及脊髓运动的种群 神经元，旨在具有临床上有益作用的方式。我们方法的关键要素是 意识到几乎所有针对电压依赖性通道的小分子化合物 与通道的不同门控状态差异互动，导致复杂 依赖电压波形。因此，对不同神经元类型的差异抑制可以 基于它们不同的休息潜力，动作潜力形状和射击模式 作为针对特定通道类型的存在或不存在。我们以前的经验 具有多种细胞类型，通道类型和靶向通道的药物将提供强大的 这项努力的基础。