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.
EAG钾离子选择通道是神经元的重要调控因子
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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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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