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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.

乙醚-a-go-go(EAG)钾选择通道是神经元的重要调节器兴奋性和癌症进展。与EAG渠道功能缺陷有关患有神经系统疾病和癌症。尽管EAG在生理上很重要细胞内配体对EAG通道的调控及其分子机制临床相关的EAG经络调节剂尚不为人所知。这项提议的目标是揭示细胞内配体调节EAG通道的分子机制最近由我们实验室发现，并确定这些药物的治疗潜力配基用于治疗与EAG经络有关的疾病。在具体目标1中，我们计划解决细胞内Per-Arnt-Sim(PAS)和环核苷酸的X射线结构- 与新近鉴定的EAG通道结合的同源结构域并对配体与Pas和Pas的结合进行计算模拟 CNBH结构域揭示EAG通道调控的结构基础细胞内的配体。然后，结构发现将被用作路线图以指导三七总皂甙调节EAG通道分子机制的功能实验配基。在具体目标2中，我们计划使用表面等离子体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被识别的PAS/CNBH结构域界面的加强或减弱监管者对EAG渠道的作用。在特定的目标3中，我们计划使用纸巾培养和斑马鱼异种移植模型测试已鉴定的癌症治疗的监管机构。这些研究的结果将对理解EAG及相关视网膜色素蛋白和麋鹿的基本调控机制为实现EAG经络调节剂的治疗潜力。