Modulation and Resistance of Levamisole Receptor Channels
左旋咪唑受体通道的调节和抵抗
基本信息
- 批准号:7555947
- 负责人:
- 金额:$ 27.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-01-01 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:AF2AF2 neuropeptideAcetylcholineAddressAffectAnimalsAnthelminticsAscariasisAscaris suumBiochemicalCaenorhabditis elegansCalciumCalcium ChannelCellular biologyCholinergic ReceptorsCyclic AMPDataDevelopmentDiarrheaDrug ModulationDrug usageElectrophysiology (science)ElementsEnvironmentFundingGoalsGrowthHandHealthHookworm InfectionsHourHumanIndividualInfantIntestinesIon ChannelIowaKnowledgeLeadLevamisoleLifeMeasuresMethodsModelingMolecularMuscleNematodaNeurosciencesNicotineParasite resistanceParasitesParasitic nematodePatch-Clamp TechniquesPathway interactionsPermeabilityPharmaceutical PreparationsPharmacologyPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiologicalPopulationPopulation CharacteristicsPositioning AttributePreparationPrincipal InvestigatorPropertyPublicationsPublishingPyrantelReportingResearchResearch PersonnelResistanceSeriesSignal PathwaySiteStructureTechniquesTechnologyTestingTherapeutic EffectUniversitiesVesicleVoltage-Clamp TechnicsWorkbasecholinergiccombatdesignimprovedinnovationlevamisole resistancemethod developmentmethyridinemutantnovelnovel strategiesnovel therapeuticsparaherquamidepatch clampprogramsreceptorresearch studyresponsetherapeutic targetvoltagevoltage clamp
项目摘要
Ascariasis and hookworm infection affect 1.6 billion people across the world. Anthelmintics, including
levamisole and related drugs (pyrantel), are used to combat nematode parasites, and resistance is a threat.
Our long-range objective is to improve human health by increasing the efficacy of anthelmintic drugs by
identifying approaches to reverse resistance. The objective of this application is to test single-channel
properties of levamisole receptors and a model that describes changes in the sensitivity of nematodes to
levamisole and alters potency. Our central hypothesis is that the structure and pore of the L-subtype
acetylcholine receptor ion-channel on nematode muscle makes it more sensitive to levamisole and more
permeable to Ca; and the increased response of acetylcholine channels (modulation) produced by the
neuropeptide, AF2,involves cAMP, Ca entry and kinase activity. The rationale for the research is that, as the
mechanisms for modulating responses to levamisole activated receptor channels become known,
pharmacological approaches can be formulated to overcome resistance. We will use muscle preparations of
A. suum, C. elegans and null-mutants with current-clamp, voltage-clamp and patch-clamp technology to test
the Ca permeability and subunit composition of L-subtype acetylcholine channels and to test a model for AF2
modulation. We will pursue 3 aims: 1) determine the Ca permeability of N-, L- and B- subtypes of A. suum
muscle acetylcholine receptors and thereby identify a preferred target site; 2) determine in patch-clamp
experiments in C. elegans, the subunit requirements of the L-subtype acetylcholine channel; 3) characterize,
n A. suum muscle, the mechanism & pharmacology by which calcium and AF2 affect the opening of different
AChR channel subtypes, in order to increase responses and potency of cholinergic anthelmintics. The
research is innovative because we are combining new knowledge from C. elegans with advanced
electrophysiology of nematode parasites including muscle-vesicle preparations for patch-clamp recordings.
We expect the research to identify additional strategies that increase the potency of cholinergic
anthelmintics. The research is significant because application of the results will to lead to new approaches
to control and overcome resistance to anthelmintics of the levamisole class.
蛔虫病和钩虫感染影响着全世界 16 亿人。驱虫药,包括
左旋咪唑和相关药物(噻嘧啶)用于对抗线虫寄生虫,耐药性是一个威胁。
我们的长期目标是通过提高驱虫药物的功效来改善人类健康
确定扭转阻力的方法。该应用程序的目的是测试单通道
左旋咪唑受体的特性和描述线虫敏感性变化的模型
左旋咪唑并改变效力。我们的中心假设是 L 亚型的结构和孔隙
线虫肌肉上的乙酰胆碱受体离子通道使其对左旋咪唑等更敏感
对 Ca 具有渗透性;以及乙酰胆碱通道(调节)的反应增加
神经肽 AF2 涉及 cAMP、Ca 内流和激酶活性。该研究的基本原理是,由于
调节左旋咪唑激活受体通道反应的机制已为人所知,
可以制定药理学方法来克服耐药性。我们将使用以下肌肉制剂
使用电流钳、电压钳和膜片钳技术测试 A. suum、C. elegans 和无效突变体
L 亚型乙酰胆碱通道的 Ca 渗透性和亚基组成并测试 AF2 模型
调制。我们将追求 3 个目标:1) 确定 A. suum N-、L- 和 B- 亚型的 Ca 渗透性
肌肉乙酰胆碱受体,从而识别优选的靶位点; 2) 膜片钳测定
线虫实验,L-亚型乙酰胆碱通道的亚基需求; 3)表征,
n A. suum 肌肉,钙和 AF2 影响不同组织开放的机制和药理学
AChR 通道亚型,以增加胆碱能驱虫药的反应和效力。这
研究具有创新性,因为我们将线虫的新知识与先进的技术相结合
线虫寄生虫的电生理学,包括用于膜片钳记录的肌囊泡制剂。
我们期望该研究能够确定增加胆碱能效力的其他策略
驱虫药。这项研究意义重大,因为结果的应用将带来新的方法
控制和克服对左旋咪唑类驱虫药的耐药性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Richard John Martin', 18)}}的其他基金
Slo-1K channels, TRP-2 channels, emodepside and diethylcarbamazine in Filaria
丝虫中的 Slo-1K 通道、TRP-2 通道、艾默德苷和二乙基卡马嗪
- 批准号:
10683137 - 财政年份:2020
- 资助金额:
$ 27.55万 - 项目类别:
Slo-1K channels, TRP-2 channels, emodepside and diethylcarbamazine in Filaria
丝虫中的 Slo-1K 通道、TRP-2 通道、艾默德苷和二乙基卡马嗪
- 批准号:
10089614 - 财政年份:2020
- 资助金额:
$ 27.55万 - 项目类别:
Slo-1K channels, TRP-2 channels, emodepside and diethylcarbamazine in Filaria
丝虫中的 Slo-1K 通道、TRP-2 通道、艾默德苷和二乙基卡马嗪
- 批准号:
10264892 - 财政年份:2020
- 资助金额:
$ 27.55万 - 项目类别:
Slo-1K channels, TRP-2 channels, emodepside and diethylcarbamazine in Filaria
丝虫中的 Slo-1K 通道、TRP-2 通道、艾默德苷和二乙基卡马嗪
- 批准号:
10468815 - 财政年份:2020
- 资助金额:
$ 27.55万 - 项目类别:
Diethylcarbamazine, Emodepside and SLO-1 K Channels of Filaria
二乙基卡马嗪、艾莫德苷和丝虫的 SLO-1 K 通道
- 批准号:
9807551 - 财政年份:2019
- 资助金额:
$ 27.55万 - 项目类别:
Membrane Ion-channels in Helminth Parasites: Anthelmintic Resistance and Sites of
蠕虫寄生虫中的膜离子通道:驱虫药耐药性和位点
- 批准号:
8203993 - 财政年份:2011
- 资助金额:
$ 27.55万 - 项目类别:
Pharmacological Diversity of nAChRs in Clade III Nematodes: Levamisole receptors
进化枝 III 线虫中 nAChR 的药理学多样性:左旋咪唑受体
- 批准号:
8605493 - 财政年份:2001
- 资助金额:
$ 27.55万 - 项目类别:
Modulation and Resistance of Levamisole Receptor Channels
左旋咪唑受体通道的调节和抵抗
- 批准号:
7339825 - 财政年份:2001
- 资助金额:
$ 27.55万 - 项目类别:
相似海外基金
Modulation and Resistance of Levamisole Receptor Channels
左旋咪唑受体通道的调节和抵抗
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7339825 - 财政年份:2001
- 资助金额:
$ 27.55万 - 项目类别:
Modulation and Resistance of Levamisole Receptor Channels
左旋咪唑受体通道的调节和抵抗
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左旋咪唑受体通道的调节和抵抗
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