Exploiting toxins to probe sensory signaling
利用毒素来探测感觉信号
基本信息
- 批准号:7740424
- 负责人:
- 金额:$ 33.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2013-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAfferent NeuronsAnalgesicsAnimalsArchitectureBindingBiochemicalBiological AssayBiological ModelsCalciumCapsaicinCardiovascular PhysiologyCell Surface ReceptorsCellsChemical AgentsChili PepperChinese PeopleCollectionCommunicationCrustaceaCysteineDataDeerDetectionEsthesiaExtended FamilyFamilyGenus MenthaGoalsHearingHeatingImageIon ChannelIonsIrritantsLabelLaboratoriesLateralLeftLigandsMammalsMapsMechanicsMentholMindModalityMolecularMorphineNerve FibersNervous system structureNeurogenic InflammationNeuronsNociceptionOpioid ReceptorOpiumOrganismOsmotic PressurePainPapaverPathway interactionsPeptidesPharmacopoeiasPhysiologicalPlantsPlayPotassiumProcessProductionProteinsProtocols documentationPublic HealthRecombinantsRoleSensorySensory Nerve EndingsSensory ReceptorsSignal TransductionSignaling MoleculeSiteSmooth Muscle MyocytesSpecific qualifier valueSpidersSquirrelStimulusStretchingStructureSyndromeTRP channelTRPV1 geneTargeted ToxinsTertiary Protein StructureTherapeutic AgentsTouch sensationToxinTreatment ProtocolsVenomsWest IndiesWillowWorkafferent nervecapsaicin receptorchronic paindesignhanatoxinhigh throughput screeningin vitro Modelinflammatory paininhibitor/antagonistinsightirritationmembernovelnovel therapeuticspressurepublic health relevanceradioligandreceptorreceptor structure functionresearch studysalicylatesensory stimulussomatosensorysuccesstooltool developmentvoltagevoltage gated channelward
项目摘要
DESCRIPTION (provided by applicant): Natural plant products have served as tremendously valuable tools for deciphering cellular and molecular mechanisms contributing to somatosensation, nociception, and pain. Notable examples include the use of natural analgesics, such as morphine (from the opium poppy) and salicylate (from willow bark) to discover opioid receptors and cyclooxgenases, respectively. Other important examples include the use of natural irritants, such as capsaicin (from chili peppers) and menthol (from mint leaves) to identify ion channels that detect heat and cold, respectively. Indeed, each of these proteins represents a validated or potential target for pharmacological management of acute or chronic pain. Plants are not unique in their capacity to produce chemical agents that target sensory neurons or other excitable cells. Indeed, venoms from vertebrate organisms (ranging from crustaceans to mammals) represent a vast pharmacopoeia that has great potential to yield novel agents with which to identify or characterize receptors, ion channels, or other signaling molecules that contribute to sensory transduction. With this in mind, we have recently discovered a novel family of peptide toxins from tarantula that activate the capsaicin receptor, TRPV1, to produce inflammatory pain (presumably as part of the spider's defensive strategy to ward off predators). These so-called vanillotoxins are the first peptide toxins known to interact with TRPV1, or for that matter, any member of the extended family of excitatory TRP channels. This proposal builds on our initial discovery of the vanillotoxins, with the goal of using natural toxins and synthetic derivatives to probe the structure and/or function of TRP channels or other receptors expressed by primary afferent neurons or other types of excitable cells. The first aim of this proposal is geared towards exploiting the vanillotoxins as novel biochemical tools with which to probe TRPV1 channel structure, beginning with experiments designed to map sites of vanillotoxin-TRPV1 interaction. Little is currently known about TRP channel architecture or gating mechanisms, and comparison of our findings with data from the voltage-gated channel field will provide valuable insights into these and related structure-function questions. The second and third aims are directed towards identifying and characterizing novel toxins from a variety of venomous creatures that target TRPV1 or other sites on excitable cells. This will expand the repertoire of pharmacological agents with which to study known or novel sensory receptors, including those that contribute to the very important, but still enigmatic process of mechanotransduction. PUBLIC HEALTH RELEVANCE Cell surface receptors and ion channels play essential roles in cellular communication throughout the body, including many aspects of nervous system and cardiovascular function. In this proposal, we describe strategies for exploiting natural toxins as new biochemical tools with which to study the structure and function of receptors and ion channels that contribute to the detection of sensory stimuli, particularly in relationship to pain sensation. Results from this work will provide a more in-depth understanding of how these receptors and channels respond to noxious (pain-producing) stimuli under normal and pathological conditions, all of which is relevant to elucidating processes that contribute to acute and chronic pain. Results from these studies may provide insights into strategies for developing novel therapeutic agents or protocols for the treatment of chronic pain syndromes.
描述(由申请人提供):天然植物产品已经成为非常有价值的工具,用于破译身体感觉、伤害感觉和疼痛的细胞和分子机制。值得注意的例子包括使用天然镇痛药,如吗啡(来自罂粟)和水杨酸(来自柳树皮),分别发现阿片受体和环氧化酶。其他重要的例子包括使用天然刺激物,如辣椒素(来自辣椒)和薄荷醇(来自薄荷叶)来识别分别探测热和冷的离子通道。事实上,这些蛋白质中的每一种都代表了急性或慢性疼痛的药理学管理的有效或潜在目标。植物并不是唯一能够产生针对感觉神经元或其他可兴奋细胞的化学物质的植物。事实上,脊椎动物(从甲壳类动物到哺乳动物)的毒液代表了一个巨大的药典,它具有巨大的潜力,可以产生用于识别或表征受体、离子通道或其他有助于感觉转导的信号分子的新药。考虑到这一点,我们最近从狼蛛身上发现了一种新的肽毒素家族,它可以激活辣椒素受体TRPV1,产生炎症性疼痛(可能是蜘蛛抵御捕食者的防御策略的一部分)。这些所谓的香草毒素是已知的第一个与TRPV1相互作用的肽毒素,或者就这一点而言,是兴奋性TRP通道大家庭的任何成员。这一建议建立在我们最初发现香草毒素的基础上,目的是利用天然毒素和合成衍生物来探测TRP通道或其他由初级传入神经元或其他类型的可兴奋细胞表达的受体的结构和/或功能。本提案的第一个目标是利用香草毒素作为新型生化工具来探测TRPV1通道结构,首先设计实验来绘制香草毒素-TRPV1相互作用的位点。目前对TRP通道结构或门控机制知之甚少,将我们的发现与电压门控通道领域的数据进行比较,将为这些和相关的结构-功能问题提供有价值的见解。第二个和第三个目标是识别和表征来自各种有毒生物的新毒素,这些毒素靶向TRPV1或可兴奋细胞上的其他位点。这将扩大用于研究已知或新的感觉受体的药理学试剂的范围,包括那些对非常重要但仍然神秘的机械转导过程有贡献的药物。细胞表面受体和离子通道在整个身体的细胞通讯中起着至关重要的作用,包括神经系统和心血管功能的许多方面。在本提案中,我们描述了开发天然毒素作为新的生化工具的策略,用于研究有助于检测感觉刺激的受体和离子通道的结构和功能,特别是与疼痛感觉有关。这项工作的结果将提供更深入的了解这些受体和通道如何在正常和病理条件下对有害(产生疼痛)刺激作出反应,所有这些都与阐明导致急性和慢性疼痛的过程有关。这些研究的结果可能为开发新的治疗药物或治疗慢性疼痛综合征的方案提供见解。
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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David Julius其他文献
David Julius的其他文献
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{{ truncateString('David Julius', 18)}}的其他基金
Natural products as probes of the pain pathway
天然产物作为疼痛通路的探针
- 批准号:
10318584 - 财政年份:2017
- 资助金额:
$ 33.29万 - 项目类别:
Natural products as probes of the pain pathway
天然产物作为疼痛通路的探针
- 批准号:
10054206 - 财政年份:2017
- 资助金额:
$ 33.29万 - 项目类别:
Natural products as probes of the pain pathway
天然产物作为疼痛通路的探针
- 批准号:
10548116 - 财政年份:2017
- 资助金额:
$ 33.29万 - 项目类别:
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