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:
- 金额:$ 60.31万
- 依托单位:
- 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:
- 关键词:Adverse effectsAffectAntibodiesApoptosisBindingBinding SitesBrainC-terminalCancer cell lineCellular biologyChemicalsComputer SimulationComputing MethodologiesCyclic NucleotidesDefectDevelopmentDiseaseDrug TargetingElectrodesElectrophysiology (science)EmbryoEthersFDA approvedGeometryGoalsGrowthHumanImplantIndividualKnock-outLaboratoriesLearningLigand BindingLigandsLinkMalignant NeoplasmsMapsMethodsMolecularMolecular Mechanisms of ActionMonitorMusMutationN-terminalNeoplasm MetastasisNeuronsPatch-Clamp TechniquesPatientsPharmaceutical PreparationsPhysiologicalPotassiumProliferatingRegulationReportingRoentgen RaysSiteSmall Interfering RNASmall Molecule Chemical LibraryStructureSubcellular structureSurface Plasmon ResonanceTechniquesTechnologyTestingTherapeuticX-Ray CrystallographyXenograft ModelXenograft procedureZebrafishcancer therapyclinically relevantcytotoxicitydrug developmentexperienceexperimental studyinhibitorinnovationmalignant neurologic neoplasmsmigrationneoplastic cellnervous system disorderneuronal excitabilityneuronal tumornoveloverexpressionsmall moleculetherapeutic evaluationtissue culturetumortumor growthtumor progressiontumorigenesisvoltage/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。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Tinatin I Brelidze', 18)}}的其他基金
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
- 批准号:
10393686 - 财政年份:2021
- 资助金额:
$ 60.31万 - 项目类别:
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
- 批准号:
10231407 - 财政年份:2021
- 资助金额:
$ 60.31万 - 项目类别:
KCNH channel regulation by intracellular ligands
细胞内配体对 KCNH 通道的调节
- 批准号:
10372601 - 财政年份:2018
- 资助金额:
$ 60.31万 - 项目类别:
KCNH channel regulation by intracellular ligands
细胞内配体对 KCNH 通道的调节
- 批准号:
10581873 - 财政年份:2018
- 资助金额:
$ 60.31万 - 项目类别:
KCNH channel regulation by intracellular ligands
细胞内配体对 KCNH 通道的调节
- 批准号:
10375400 - 财政年份:2018
- 资助金额:
$ 60.31万 - 项目类别:
KCNH channel regulation by intracellular ligands
细胞内配体对 KCNH 通道的调节
- 批准号:
9896844 - 财政年份:2018
- 资助金额:
$ 60.31万 - 项目类别:
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