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:10393686
- 负责人:
- 金额:$ 51.55万
- 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 MethodologiesCrystallizationCyclic NucleotidesDefectDevelopmentDiseaseDrug TargetingElectrodesElectrophysiology (science)EmbryoEthersFDA approvedGeometryGoalsGrowthHumanImplantIndividualKnock-outLaboratoriesLearningLigand BindingLigandsLinkMalignant NeoplasmsMapsMethodsMolecularMolecular Mechanisms of ActionMonitorMusMutationN-terminalNeoplasm MetastasisNeuronsPatch-Clamp TechniquesPatientsPharmaceutical PreparationsPhysiologicalPotassiumRegulationReportingRoentgen 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 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)钾离子通道是神经元电生理的重要调节因子,
兴奋性和癌症进展。EAG通道功能缺陷与
患有神经系统疾病和癌症尽管EAG的生理重要性
通道,EAG通道调节细胞内配体的分子机制,
临床相关的EAG通道调节剂是未知的。本提案的目的是
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,并确定这些治疗潜力,
用于治疗与EAG通道相关的疾病的配体。具体目标1:
解决了细胞内Per-Arnt-Sim(PAS)和环核苷酸的X射线结构,
结合同源性(CNBH)结构域的EAG通道结合到最近确定的
配体,并进行配体与PAS结合的计算模拟,
CNBH结构域,以揭示EAG通道调节的结构基础,
胞内配体。然后,结构性调查结果将被用作指导
EAG通道调节的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
接口.然后,我们将使用电生理学来确定
PAS/CNBH结构域界面的增强或减弱,
调节EAG通道的功能。在Specific Aim 3中,我们计划使用组织
培养物和斑马鱼异种移植物模型,以测试所鉴定的
用于治疗癌症的调节剂。这些研究的结果将是至关重要的
了解EAG及相关ERG和ELK的基本调节机制
通道,并用于获得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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会议论文数量(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:
10231407 - 财政年份:2021
- 资助金额:
$ 51.55万 - 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:
10593928 - 财政年份:2021
- 资助金额:
$ 51.55万 - 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:
$ 51.55万 - 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:
$ 51.55万 - 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:
$ 51.55万 - 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:
$ 51.55万 - 项目类别:
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