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Functional mechanisms and therapeutic potential of EAG channel regulators

EAG通道调节剂的功能机制和治疗潜力

基本信息

批准号：
10593928
负责人：
Tinatin I Brelidze
金额：
$ 60.31万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593928
关键词：
Adverse effects Affect Antibodies Apoptosis Binding Binding Sites Brain C-terminal Cancer cell line Cellular biology Chemicals Computer Simulation Computing Methodologies Cyclic Nucleotides Defect Development Disease Drug Targeting Electrodes Electrophysiology (science)Embryo Ethers FDA approved Geometry Goals Growth Human Implant Individual Knock-out Laboratories Learning Ligand Binding Ligands Link Malignant Neoplasms Maps Methods Molecular Molecular Mechanisms of Action Monitor Mus Mutation N-terminal Neoplasm Metastasis Neurons Patch-Clamp Techniques Patients Pharmaceutical Preparations Physiological Potassium Proliferating Regulation Reporting Roentgen Rays Site Small Interfering RNA Small Molecule Chemical Library Structure Subcellular structure Surface Plasmon Resonance Techniques Technology Testing Therapeutic X-Ray Crystallography Xenograft Model Xenograft procedure Zebrafish cancer therapy clinically relevant cytotoxicity drug development experience experimental study inhibitor innovation malignant neurologic neoplasms migration neoplastic cell nervous system disorder neuronal excitability neuronal tumor novel overexpression small molecule therapeutic evaluation tissue culture tumor tumor growth tumor progression tumorigenesis voltage/patch clamp

项目摘要

Ether-a-go-go (EAG) potassium selective channels are important regulators of neuronal excitability and cancer progression. Defects in EAG channel function are associated with neurological disorders and cancer. Despite the physiological importance of EAG channels, molecular mechanisms of EAG channel regulation by intracellular ligands and clinically relevant EAG channel regulators are not known. The goal of this proposal is to uncover molecular mechanisms of EAG channel regulation by intracellular ligands recently discovered by our laboratory and to determine a therapeutic potential of these ligands for treatment of diseases linked to EAG channels. In Specific Aim 1 we plan to solve X-ray structures of the intracellular Per-Arnt-Sim (PAS) and cyclic nucleotide- binding homology (CNBH) domains of EAG channels bound to the recently identified ligands and conduct computational simulations of the ligand binding to the PAS and CNBH domains to uncover the structural basis of EAG channel regulation by the intracellular ligands. The structural findings will be then used as a road map to guide functional experiments on the molecular mechanisms of EAG channel regulation by the ligands. In Specific Aim 2 we plan to use surface plasmon resonance method to identify novel EAG channel ligands that affect channel function through PAS and CNBH domain interface. We will then use electrophysiology to determine functional implications of strengthening or weakening of the PAS/CNBH domain interface by the identified regulators on the function of EAG channels. In Specific Aim 3 we plan to use tissue culture and zebrafish xenograft models to test therapeutic potential of the identified regulators for treatment of cancer. The results of these studies will be crucial for understanding fundamental regulatory mechanisms of EAG and related ERG and ELK channels, and for attaining therapeutic potential of EAG channel regulators.

EAG钾离子选择通道是神经元的重要调控因子