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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.

Ether-a-go-go (EAG) 钾选择性通道是神经元的重要调节剂兴奋性和癌症进展。 EAG 通道功能缺陷相关患有神经系统疾病和癌症。尽管 EAG 具有生理重要性通道、细胞内配体调节 EAG 通道的分子机制和临床相关的 EAG 通道调节剂尚不清楚。该提案的目标是揭示细胞内配体调节 EAG 通道的分子机制我们的实验室最近发现并确定了这些药物的治疗潜力用于治疗与 EAG 通道相关的疾病的配体。在具体目标 1 中，我们计划解析细胞内 Per-Arnt-Sim (PAS) 和环核苷酸的 X 射线结构 EAG 通道的结合同源 (CNBH) 域与最近识别的配体并对配体与 PAS 的结合进行计算模拟 CNBH 域揭示 EAG 通道调节的结构基础细胞内配体。然后，结构发现将用作路线图来指导 EAG通道调节分子机制的功能实验配体。在具体目标2中，我们计划使用表面等离子共振方法来识别通过 PAS 和 CNBH 结构域影响通道功能的新型 EAG 通道配体界面。然后我们将使用电生理学来确定通过确定的增强或削弱 PAS/CNBH 域界面调节器对 EAG 通道功能的影响。在具体目标 3 中，我们计划使用纸巾培养和斑马鱼异种移植模型来测试已识别的治疗潜力癌症治疗的调节剂。这些研究的结果对于了解 EAG 以及相关 ERG 和 ELK 的基本调节机制通道，并获得 EAG 通道调节剂的治疗潜力。