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

基本信息

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
项目类别：
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

项目摘要

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对控制K2P（KCNK）钾通道功能的基本机制发展理解，并开发方法来识别和表征K2P家族的小分子，离子通道调节剂。 K2P是一个多元化的钾选择性通道，负责背景“泄漏”电流。这些电流在调节神经元的兴奋性方面至关重要。 K2P对包括pH变化，温度和机械力的各种刺激做出了反应。尽管K2P在神经和心血管系统中具有完善的角色，并且与疼痛，麻醉反应，热增效和情绪有关，但它们是最不受欢迎的钾通道类。离子通道是令人垂涎的药物靶标。作为膜蛋白，它们很容易被细胞外化合物访问，并且调节会带来心脏和大脑中可激发细胞的性质的快速变化。但是，作为膜蛋白，它们也居住在许多需要纯化材料的调节剂开发方法之外。因此，许多渠道，包括K2P家族中的渠道，缺乏大量的药理学。这个问题导致我们将离子通道基因与体内功能连接的能力存在差距。我们正在采用一种多学科方法，其中包括遗传选择，生物物理和电生理测量值，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活性的新的小分子。定义控制K2P活性并发现新的K2P调节器的分子机制应提供关键框架和必要的工具，以了解K2PS的功能。由于它们在人类生理学中的重要作用，K2P是治疗慢性疼痛，中风和抑郁症的药物的靶标。因此，对K2PS的功能和手段进行了解以及影响通道功能的小分子的理解不仅应提供剖析K2P机制的强大工具，而且还应有助于开发新的治疗剂来为一系列人类疾病开发。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标。我们的工作旨在了解控制一个被称为K2P的家族功能的基本机制，这些机制涉及热，机械和化学传感，并开发影响通道功能的新型试剂。这种知识和试剂在开发神经系统和心血管疾病的更有效治疗方面具有直接相关性。