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: 8233320
• 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/8233320
• 关键词: Address; Affect; Alleles; Anesthetics; Arrhythmia; Behavior; Biological; Biological Process; Biophysics; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Cognition; Development; Drug Delivery Systems; 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）：本项目的长期目标是了解控制K2P（KCNK）钾通道功能的基本机制，并开发鉴定和表征K2P家族小分子离子通道调节剂的方法。K2Ps是一个多样化的钾离子选择性通道家族，负责背景“泄漏”电流。这些电流是调节神经元兴奋性的关键。K2Ps对不同的刺激有反应，包括pH变化、温度和机械力。尽管K2Ps在神经和心血管系统中具有公认的作用，并与疼痛、麻醉反应、温度感觉和情绪有关，但它们是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近，它们的调节引起心脏和大脑中可兴奋细胞性质的快速变化。然而，作为膜蛋白，它们也超出了许多用于需要纯化材料的调节剂开发的成熟方法。因此，许多通道，包括K2P家族中的通道，缺乏显著的药理学作用。这个问题导致我们在连接离子通道基因与体内功能的能力上存在差距。我们正在寻求一种多学科的方法，包括遗传选择，生物物理和电生理测量，以识别，解剖和表征控制K2P功能的核心元素，并定义和表征控制K2P活性的新小分子。确定控制K2P活性的分子机制和发现新的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工具。由于它们在人体生理学中的重要作用，K2Ps是治疗慢性疼痛、中风和抑郁症的药物的靶点。因此，了解K2Ps如何发挥作用以及找到影响通道功能的小分子的方法不仅可以为剖析K2P机制提供强大的工具，还可以帮助开发用于一系列人类疾病的新治疗药物。 公共卫生相关性：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点。我们的工作旨在了解控制离子通道家族（称为K2Ps）功能的基本机制，这些离子通道参与热，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神经系统和心血管疾病的更有效治疗方法直接相关。