Molecular and Cellular signaling mechanisms of TRPV4 in non-neuronal cells: a pathophysiological relevance for migraine pain.
非神经元细胞中 TRPV4 的分子和细胞信号传导机制:与偏头痛的病理生理学相关性。
基本信息
- 批准号:10371665
- 负责人:
- 金额:$ 19.44万
- 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:2021-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAfferent NeuronsAfrican AmericanAfrican American populationAmplifiersAnimal BehaviorAnimal ModelApplications GrantsAreaAttenuatedBasic ScienceBiologicalBiological AssayCaucasiansCell DegranulationCell LineCell LineageCellsCholic AcidsCoculture TechniquesCollaborationsCommunicationComplexDermatologyDevelopmentDevelopment PlansDinoprostoneDisciplineDoseEnvironmentExposure toFunctional disorderFutureGene TargetingGenesGoalsHeadHeadacheHumanHypersensitivityIL6 geneImmunologyInflammationInflammatoryInterleukin-1 betaIon ChannelLaboratoriesLeadershipLysophosphatidylcholinesMeasuresMediator of activation proteinMedicineMelaninsMeningealMeningesMentorsMigraineMolecularMusNeurogliaNeurologyNeuronsNociceptionNociceptorsPainPathologicPathway interactionsPermeabilityPhosphotransferasesPhysiological ProcessesPigmentation physiologic functionPlayPositioning AttributePrincipal InvestigatorProcessRaceRegulationResearchResearch PersonnelRoleSeveritiesSignal TransductionSkinSkin PigmentationStatistical Data InterpretationTNF geneTechniquesTestingTimeTopical applicationTrainingTranslational ResearchTrigeminal PainTrigeminal SystemUVB inducedUltraviolet B RadiationUniversitiesWritingbasecareercareer developmentexperienceexperimental studyface skinin vivoinflammatory paininhibitorinterdisciplinary approachkeratinocyteloss of functionmast cellnervous system disorderneuronal excitabilitypain signalparacrinepeer networkspersonalized medicineprecursor cellracial differencereceptorresponseskillsspellingsupportive environmenttissue injury
项目摘要
ABSTRACT
Transient receptor potential (TRP) ion channels have been implicated in the pathophysiology of migraine, a
neurological disorder with incapacitating episodic headaches. TRPV4 Ca++-permeable ion channels are
expressed and function in trigeminal (TG) sensory neurons, also in keratinocytes and in mast cells, which are
both innervated by TG sensory neurons, in head-face skin and meninges. My main objective is to define TRPV4
dependent mechanisms in non-neuronal cells, specifically skin keratinocytes and meningeal mast cells, and how
these can tune migraine pain-relevant trigeminal nociceptor neurons. One particular intriguing and understudied
feature of migraine and other pathologic pain is racial divergence of suffering, identified as more severe in African
Americans. An obstacle toward rational understanding is simply a lack of mechanistic studies that elucidate this
phenomenon. Based on my preliminary experiments, namely TRPV4 channels becoming UVB-sensitized more
in skin keratinocytes from African Americans than from Caucasians, I also intend to elucidate racial differences
in forefront trigeminal pain signaling that depend on TRPV4 in keratinocytes and mast cells. My central
hypothesis is that hypersensitization of TRPV4 channels in skin keratinocytes and meningeal mast cells
contributes to development and perpetuation of inflammatory pain in migraine, and that this regulation is
modulated by racial background. To test this hypothesis, I propose two aims: 1) To determine how inflammation
alters TRPV4 channel sensitization in keratinocytes and how skin pigmentation determines the channel’s
sensitivity; 2) To characterize the contribution of TRPV4 in mast cells in migraine pain. Yield from this proposal
will fill a significant gap in understanding how TRPV4 facilitates the crosstalk of keratinocytes and mast cells with
TG neurons that innervate them and contribute to the pathophysiology of migraine. Deconstructing these
processes will set the stage for regulating both mast cells’ and keratinocytes’ powerful pro-inflammatory/pro-
algesic organismal function. The proposed quest for identifiable racial differences of biologic signaling in the
interrogated cell lineages will position us to leverage these findings toward personalized medicine.
With the guidance from my team of mentors, whose expertise ranges across the pertinent areas of study relevant
for this proposal, and with whom I am already effectively collaborating, I propose to effectively train for my further
career development. I expect to: 1) Gain experience in collaborations and team formation, 2) Expand my skill-
set platform in laboratory-based techniques such as modeling animal behavior and mast cell cellular and
molecular assays, 3) Acquire and apply advance statistical analysis skills to my research, 4) Expand my
communication skills, including scientific writing and presentation, and build on my existing set of managerial
and leadership skills. The proposed training will equip me with unique a set of skills needed to become an
Independent laboratory-based investigator in multidisciplinary approaches for studying inflammatory pain.
抽象的
瞬时受体电位 (TRP) 离子通道与偏头痛的病理生理学有关,偏头痛是一种
伴有阵发性头痛的神经系统疾病是 TRPV4 Ca++ 渗透性离子通道。
在三叉神经 (TG) 感觉神经元、角质形成细胞和肥大细胞中表达和发挥作用,这些细胞是
头面部皮肤和脑膜均受 TG 感觉神经元支配。我的主要目标是定义 TRPV4。
非神经元细胞,特别是皮肤角质形成细胞和脑膜肥大细胞的依赖机制,以及如何
这些可以调节与偏头痛相关的三叉神经伤害感受器神经元,这是一种特别有趣且尚未研究的神经元。
偏头痛和其他病理性疼痛的特点是痛苦的种族差异,非洲人的痛苦更为严重
美国人理性理解的一个障碍就是缺乏阐明这一点的机制研究。
根据我的初步实验,TRPV4 通道对 UVB 更加敏感。
非裔美国人的皮肤角质形成细胞与白种人的皮肤角质形成细胞相比,我还打算阐明种族差异
位于最前沿的三叉神经疼痛信号传导依赖于角质形成细胞和肥大细胞中的 TRPV4。
假设皮肤角质形成细胞和脑膜肥大细胞中 TRPV4 通道超敏化
有助于偏头痛炎症性疼痛的发展和持续,并且这种调节是
为了检验这个假设,我提出了两个目标:1)确定炎症是如何发生的。
改变角质细胞中 TRPV4 通道的敏感性以及皮肤色素沉着如何决定该通道的
敏感性;2) 表征肥大细胞中 TRPV4 对偏头痛的影响。
将填补理解 TRPV4 如何促进角质形成细胞和肥大细胞与
TG 神经元支配它们并促成偏头痛的病理生理学。
这些过程将为调节肥大细胞和角质形成细胞强大的促炎/促炎症奠定基础。
所提出的对生物信号传导的可识别种族差异的探索。
研究细胞谱系将使我们能够利用这些发现来实现个性化医疗。
在我的导师团队的指导下,他们的专业知识涵盖相关的研究领域
对于这项提案,并且我已经与他们进行了有效的合作,我建议为我的进一步培训进行有效的培训
我期望:1)获得协作和团队组建的经验,2)扩展我的技能-
建立基于实验室的技术平台,例如动物行为建模和肥大细胞和
分子测定,3) 获得先进的统计分析技能并将其应用于我的研究,4) 扩展我的研究
沟通技巧,包括科学写作和演示,并以我现有的管理能力为基础
拟议的培训将使我具备成为一名专家所需的一系列独特技能。
独立实验室研究者,采用多学科方法研究炎症性疼痛。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Carlene D Moore其他文献
Carlene D Moore的其他文献
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{{ truncateString('Carlene D Moore', 18)}}的其他基金
Molecular and Cellular signaling mechanisms of TRPV4 in non-neuronal cells: a pathophysiological relevance for migraine pain.
非神经元细胞中 TRPV4 的分子和细胞信号传导机制:与偏头痛的病理生理学相关性。
- 批准号:
10532165 - 财政年份:2021
- 资助金额:
$ 19.44万 - 项目类别:
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