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

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：
10612057
负责人：
DANIEL L MINOR
金额：
$ 76.43万
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 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612057
关键词：
Address Affect Amines Anesthetics Arrhythmia Behavior Binding Binding Sites Biochemical Biological Biology Biophysics Brain Cardiovascular Diseases Cardiovascular system Cells Chemicals Complex Cryoelectron Microscopy Development Disulfides Drug Targeting Drug usage Electrophysiology (science)Elements Engineering Environment Epilepsy Family Family member Foundations Genes Genetic Goals Heart Human Hypertension Investigation Ion Channel Ions Knowledge Lipid Binding Lipids Maps Mass Spectrum Analysis Measurement Mechanics Membrane Membrane Proteins Mental Depression Modality Modeling Molecular Molecular Conformation Mood Disorders Moods Mutagenesis Nature Nervous System Pain Pharmacology Physiology Play Potassium Potassium Channel Process Property Protein Engineering Reagent Role Ruthenium SF1 Signal Transduction Site Stimulus Stroke Structure Temperature Testing Therapeutic Agents Work X-Ray Crystallography chronic pain management computer studies design dimer efficacious treatment empowerment extracellular genetic approach human disease in vivo insight interdisciplinary approach invention mechanical force member molecular dynamics mutant nanodisk nanomolar neuronal excitability novel novel therapeutics particle potassium ion preference pressure response sensory system simulation small molecule targeted treatment tool

项目摘要

Project Summary The long-term goals of this project are to develop an understanding of the fundamental mechanisms that control the function of K2P potassium channels and to identify, develop, 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 remain 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 well-established approaches for modulator development. 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 biophysical, structural, computational, and electrophysiological measurements and chemical biology approaches to identify, dissect, and characterize the core elements that control K2P function and to define and characterize new small molecules that can 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 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.

项目总结