Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
基本信息
- 批准号:9757759
- 负责人:
- 金额:$ 69.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2019-09-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute PainAdoptedAdultAgonistAwarenessBehavior assessmentBehavioralCell membraneCell modelCellsChronicClathrinCleaved cellColonCrystallizationDrug TargetingElectrophysiology (science)EndocytosisEndosomesExocytosisFamily memberG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGenerationsHumanInflammationInflammatory Bowel DiseasesInjuryIon ChannelIrritable Bowel SyndromeKnowledgeLigand BindingLipidsMediatingMedicalMolecular ConformationMusNatureNeuronsNociceptionNociceptorsOpioidPAR-2 ReceptorPainPain managementPathologicPathologic ProcessesPathway interactionsPeptide HydrolasesPersistent painPharmaceutical PreparationsPhysiologicalPhysiological ProcessesPrevalenceProcessPropertyProteinase-Activated ReceptorsRecyclingSignal TransductionSignaling ProteinSiteStimulusTestingTherapeuticbiophysical techniqueschronic paindrug developmenteffective therapyexperimental studyextracellularimaging approachinhibitor/antagonistinsightnovel therapeuticsoverexpressionpain reliefpain signalpreventreceptorreceptor internalizationside effecttherapeutic targettraffickingtrans-Golgi Network
项目摘要
PROJECT SUMMARY
Chronic pain is a major unmet medical problem. The mechanisms that underlie the transition from acute
(physiological) to chronic (pathological) pain are poorly understood and current therapies are inadequate. The
proposal investigates colonic pain, with relevance to irritable bowel syndrome and inflammatory bowel disease.
Proteases that are activated during injury and inflammation can signal to nociceptors by cleaving protease-
activated receptor-2 (PAR2), which activates transient receptor potential channels and induces long-lasting
hyperexcitability and nociception. Although proteases and PAR2 have been implicated in colonic pain, the
signaling mechanisms that underlie persistent protease-induced pain are far from clear, and whether PAR2 is a
therapeutic target for chronic pain is uncertain. The premise is that PAR2 is uniquely suited to transmit persistent
nociception due to the irreversible mechanism of proteolytic (catalytic) activation, the capacity of the receptor to
signal from endosomes, and the efficient mechanisms that mobilize intracellular receptor stores. Accordingly,
antagonists of endosomal PAR2 and inhibitors of mobilization provide effective pain relief. These concepts will
be examined in intact mice, isolated segments of mouse and human colon, and nociceptive neurons in culture.
Approaches will include: behavioral assessment of nociception, electrophysiological analysis of nociceptor
activation, and biophysical and imaging approaches to assess PAR2 trafficking and signaling in nociceptors.
Mice expressing fluorescent PAR2 will be used to study PAR2 trafficking. Mice with targeted deletion of PAR2 on
nociceptors, and unique lipid-conjugated antagonists of endosomal PAR2, will be used to determine whether
PAR2 in endosomes of nociceptors is a therapeutic target for persistent colonic pain. The studies will provide
insights into the mechanisms and treatment of chronic pain. They have implications for therapeutic targeting of
G protein-coupled receptors; this 1,000-member family of receptors is the target of 40% of drugs. Since many
activated receptors internalize and continue to signal, effective therapy requires endosomally-targeted drugs.
项目概要
慢性疼痛是一个尚未解决的重大医学问题。从急性转变的机制
对(生理性)到慢性(病理性)疼痛的了解甚少,目前的治疗方法也不足。这
该提案调查了结肠疼痛与肠易激综合征和炎症性肠病的相关性。
在损伤和炎症过程中激活的蛋白酶可以通过裂解蛋白酶向伤害感受器发出信号
激活受体 2 (PAR2),激活瞬时受体电位通道并诱导持久
过度兴奋和伤害感受。尽管蛋白酶和 PAR2 与结肠疼痛有关,但
引起持续性蛋白酶诱导疼痛的信号传导机制尚不清楚,PAR2 是否是一种
慢性疼痛的治疗目标尚不确定。前提是 PAR2 独特地适合传输持久性
由于不可逆的蛋白水解(催化)激活机制导致的伤害感受,受体的能力
来自内体的信号,以及动员细胞内受体储备的有效机制。因此,
内体 PAR2 拮抗剂和动员抑制剂可有效缓解疼痛。这些概念将
在完整小鼠、小鼠和人类结肠的分离片段以及培养物中的伤害性神经元中进行检查。
方法包括:伤害感受的行为评估、伤害感受器的电生理分析
激活、生物物理和成像方法来评估伤害感受器中 PAR2 的运输和信号传导。
表达荧光 PAR2 的小鼠将用于研究 PAR2 运输。靶向删除 PAR2 的小鼠
伤害感受器和内体 PAR2 的独特脂质偶联拮抗剂将用于确定是否
伤害感受器内体中的 PAR2 是持续性结肠疼痛的治疗靶点。研究将提供
深入了解慢性疼痛的机制和治疗。它们对治疗靶向具有影响
G蛋白偶联受体;这个由 1,000 个成员组成的受体家族是 40% 药物的靶标。由于许多
激活的受体内化并继续发出信号,有效的治疗需要内体靶向药物。
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('NIGEL W BUNNETT', 18)}}的其他基金
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
10616927 - 财政年份:2022
- 资助金额:
$ 69.6万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
10174921 - 财政年份:2020
- 资助金额:
$ 69.6万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
10093340 - 财政年份:2020
- 资助金额:
$ 69.6万 - 项目类别:
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
10458307 - 财政年份:2020
- 资助金额:
$ 69.6万 - 项目类别:
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
9974866 - 财政年份:2020
- 资助金额:
$ 69.6万 - 项目类别:
Protease/PAR2/TRPV4 Axis and Oral Cancer Pain
蛋白酶/PAR2/TRPV4轴与口腔癌疼痛
- 批准号:
10020473 - 财政年份:2019
- 资助金额:
$ 69.6万 - 项目类别:
Protease/PAR2/TRPV4 Axis and Oral Cancer Pain
蛋白酶/PAR2/TRPV4轴与口腔癌疼痛
- 批准号:
10321672 - 财政年份:2018
- 资助金额:
$ 69.6万 - 项目类别:
Endosomal Platforms for Neuropeptide Receptor Signaling
神经肽受体信号转导的内体平台
- 批准号:
10093292 - 财政年份:2017
- 资助金额:
$ 69.6万 - 项目类别:
Endosomal Platforms for Neuropeptide Receptor Signaling
神经肽受体信号转导的内体平台
- 批准号:
10200907 - 财政年份:2017
- 资助金额:
$ 69.6万 - 项目类别:
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