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.

项目概要/摘要 拟议的工作将整合实验室中两个长期的研究方向。一是为了 理解是理解单个神经元中如何存在多种类型的离子通道 共同努力调节其射击模式。在早期的资助期间，我们专注于个人 各种钙通道、钠通道和通道的门控行为和功能作用 不同种类哺乳动物神经元中的钾通道。最近，我们尝试 了解电流如何通过给定神经元类型的多种通道 通常以令人惊讶的方式相互作用，以控制神经元的放电模式。在第二行中 研究中，我们已经表征了多种针对 电压相关通道。这项工作的大部分最初集中于寻找肽毒素和 小分子可用于从特定通道类型中分离电流成分。我们的 现在的目标是利用我们关于离子通道组成差异的不断扩展的知识 不同种类的神经元合理设计能够抑制（或增强）的新型化合物 特定种类神经元的活动。假设许多临床上的情况并非偶然—— 有效的药物作用于多个离子通道，我们将尝试设计单一化合物 故意设计来抑制或增强电压依赖性钠的特定组合， 钾和钙通道可差异性抑制（或增强）特定神经元的放电 感兴趣的类型，包括初级伤害感受器、海马和皮质锥体神经元， 不同群体的皮质和海马 GABA 能神经元以及脊髓运动 神经元，以具有临床有益效果的方式。我们方法的一个关键要素是 认识到几乎所有小分子化合物都针对电压依赖性通道 与通道的不同门控状态有不同的相互作用，导致复杂的 依赖于电压波形。因此，不同神经元类型的差异抑制可以 基于它们不同的静息电位、动作电位形状和放电模式 作为目标的特定通道类型的存在或不存在。我们之前的经验 具有一系列细胞类型、通道类型和通道靶向药物将提供强大的 为这一努力奠定了基础。