Genetic and chemical biological studies of K2P structure, function, and modulatio

K2P 结构、功能和调节的遗传和化学生物学研究

• 批准号: 8611969
• 负责人: DANIEL L MINOR
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611969
• 关键词: Address; Affect; Alleles; Anesthetics; Arrhythmia; Behavior; Biological; Biological Process; Biophysics; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Cognition; Development; Drug Targeting; Drug usage; Elements; Epilepsy; Family; Foundations; Genes; Genetic; Goals; Heart; Heating; Human; Hypertension; In Vitro; Investigation; Ion Channel; Knowledge; Maps; Measurement; Mechanics; Membrane Proteins; Mental Depression; Methods; Modality; Molecular; Mood Disorders; Moods; Mutagenesis; Nervous system structure; Neurons; Pain; Pharmacology; Physiological; Physiology; Potassium; Potassium Channel; Property; Protein Engineering; Protons; Reagent; Role; Signal Transduction; Site; Specificity; Stimulus; Stretching; Stroke; Structure; Structure-Activity Relationship; Temperature; Testing; Therapeutic Agents; Transmembrane Domain; Work; Yeasts; base; chemical genetics; chronic pain; extracellular; gain of function; gain of function mutation; genetic selection; high throughput screening; human disease; in vivo; inhibitor/antagonist; innovation; interdisciplinary approach; member; mutant; novel; novel strategies; novel therapeutics; polypeptide; portion control; public health relevance; response; sensory system; small molecule; tool

DESCRIPTION (provided by applicant): The long-term goals of this project are to develop an understanding of the fundamental mechanisms that control the function of K2P (KCNK) potassium channels and to develop methods to identify and characterize small molecule, ion channel modulators for the K2P family. K2Ps are a diverse family of potassium-selective channels that are responsible for background 'leak' currents. These currents are pivotal in modulating the excitability of neurons. K2Ps respond to varied stimuli that include pH changes, temperature, and mechanical force. Although, K2Ps have well-established roles in the nervous and cardiovascular systems and are implicated in pain, anesthetic responses, thermosensation, and mood, they are the least well-understood potassium channel class. Ion channels are coveted drug targets. As membrane proteins, they are readily accessible to extracellular compounds and their modulation brings about rapid changes in the properties of excitable cells in the heart and brain. However, as membrane proteins, they also reside beyond many of the well-established approaches for modulator development that require purified material. Consequently, many channels, including those in the K2P family, lack significant pharmacologies. This problem leads to a gap in our ability to connect ion channel genes with in vivo function. We are pursuing a multidisciplinary approach that includes genetic selections, biophysical, and electrophysiological measurements to identify, dissect, and characterize the core elements that control K2P function and to define and characterize new small molecules that control K2P activity. Defining the molecular mechanisms that control K2p activity and uncovering new K2P modulators should provide the key framework and necessary tools for understanding how K2Ps function. Because of their important roles in human physiology, K2Ps are targets for drugs for the treatment of chronic pain, stroke, and depression. Thus, developing an understanding of how K2Ps function and means to find and small molecules that affect channel function should not only provide powerful tools for dissecting K2P mechanism but should aid in the development of new therapeutic agents for a range of human diseases. PUBLIC HEALTH RELEVANCE: Ion channels are the targets of drugs used to treat pain, epilepsy, mood disorders, hypertension, and arrhythmia. Our work aims to understand the fundamental mechanisms that control the function of a family of ion channels, known as K2Ps, that are involved in thermal, mechanical, and chemical sensing and to develop novel reagents that affect channel function. Such knowledge and reagents have direct relevance for development of more efficacious treatments of nervous system and cardiovascular disorders.

描述（由申请人提供）：该项目的长期目标是加深对控制 K2P (KCNK) 钾通道功能的基本机制的了解，并开发识别和表征 K2P 家族小分子离子通道调节剂的方法。 K2P 是钾选择性通道的一个多样化家族，负责背景“泄漏”电流。这些电流对于调节神经元的兴奋性至关重要。 K2P 对各种刺激做出反应，包括 pH 值变化、温度和机械力。尽管 K2P 在神经和心血管系统中具有明确的作用，并且与疼痛、麻醉反应、热感觉和情绪有关，但它们是人们最不了解的钾通道类别。离子通道是令人垂涎的药物靶点。作为膜蛋白，它们很容易被细胞外化合物接触，并且它们的调节会导致心脏和大脑中可兴奋细胞的特性发生快速变化。然而，作为膜蛋白，它们也超出了许多需要纯化材料的成熟调节剂开发方法的范围。因此，许多通道，包括 K2P 家族中的通道，缺乏显着的药理学作用。这个问题导致我们将离子通道基因与体内功能联系起来的能力存在差距。我们正在寻求一种多学科方法，包括遗传选择、生物物理和电生理学测量，以识别、剖析和表征控制 K2P 功能的核心元素，并定义和表征控制 K2P 活性的新小分子。定义控制 K2P 活性的分子机制并发现新的 K2P 调节剂应该为理解 K2P 如何发挥作用提供关键框架和必要的工具。由于 K2P 在人体生理学中的重要作用，K2P 成为治疗慢性疼痛、中风和抑郁症药物的靶标。因此，了解 K2P 的功能以及寻找影响通道功能的小分子的方法不仅应该为剖析 K2P 机制提供强大的工具，而且应该有助于开发针对一系列人类疾病的新治疗剂。 公共健康相关性：离子通道是用于治疗疼痛、癫痫、情绪障碍、高血压和心律失常的药物的靶标。我们的工作旨在了解控制一系列离子通道（称为 K2P）功能的基本机制，这些离子通道涉及热、机械和化学传感，并开发影响通道功能的新型试剂。这些知识和试剂与开发更有效的神经系统和心血管疾病治疗方法有直接关系。