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：
Carlene D Moore
金额：
$ 19.44万
依托单位：
DUKE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10371665
关键词：
Address Affect Afferent Neurons African American African American population Amplifiers Animal Behavior Animal Model Applications Grants Area Attenuated Basic Science Biological Biological Assay Caucasians Cell Degranulation Cell Line Cell Lineage Cells Cholic Acids Coculture Techniques Collaborations Communication Complex Dermatology Development Development Plans Dinoprostone Discipline Dose Environment Exposure to Functional disorder Future Gene Targeting Genes Goals Head Headache Human Hypersensitivity IL6 gene Immunology Inflammation Inflammatory Interleukin-1 beta Ion Channel Laboratories Leadership Lysophosphatidylcholines Measures Mediator of activation protein Medicine Melanins Meningeal Meninges Mentors Migraine Molecular Mus Neuroglia Neurology Neurons Nociception Nociceptors Pain Pathologic Pathway interactions Permeability Phosphotransferases Physiological Processes Pigmentation physiologic function Play Positioning Attribute Principal Investigator Process Race Regulation Research Research Personnel Role Severities Signal Transduction Skin Skin Pigmentation Statistical Data Interpretation TNF gene Techniques Testing Time Topical application Training Translational Research Trigeminal Pain Trigeminal System UVB induced Ultraviolet B Radiation Universities Writing base career career development experience experimental study face skin in vivo inflammatory pain inhibitor interdisciplinary approach keratinocyte loss of function mast cell nervous system disorder neuronal excitability pain signal paracrine peer networks personalized medicine precursor cell racial difference receptor response skills spelling supportive environment tissue injury

Address Affect Afferent Neurons African American African American population Amplifiers Animal Behavior Animal Model Applications Grants Area Attenuated Basic Science Biological Biological Assay Caucasians Cell Degranulation Cell Line Cell Lineage Cells Cholic Acids Coculture Techniques Collaborations Communication Complex Dermatology Development Development Plans Dinoprostone Discipline Dose Environment Exposure to Functional disorder Future Gene Targeting Genes Goals Head Headache Human Hypersensitivity IL6 gene Immunology Inflammation Inflammatory Interleukin-1 beta Ion Channel Laboratories Leadership Lysophosphatidylcholines Measures Mediator of activation protein Medicine Melanins Meningeal Meninges Mentors Migraine Molecular Mus Neuroglia Neurology Neurons Nociception Nociceptors Pain Pathologic Pathway interactions Permeability Phosphotransferases Physiological Processes Pigmentation physiologic function Play Positioning Attribute Principal Investigator Process Race Regulation Research Research Personnel Role Severities Signal Transduction Skin Skin Pigmentation Statistical Data Interpretation TNF gene Techniques Testing Time Topical application Training Translational Research Trigeminal Pain Trigeminal System UVB induced Ultraviolet B Radiation Universities Writing base career career development experience experimental study face skin in vivo inflammatory pain inhibitor interdisciplinary approach keratinocyte loss of function mast cell nervous system disorder neuronal excitability pain signal paracrine peer networks personalized medicine precursor cell racial difference receptor response skills spelling supportive environment tissue injury

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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.

抽象的瞬时接收器电位（TRP）离子通道已在偏头痛的病理生理学中隐含神经系统疾病，无能力的情节标头。 TRPV4 Ca ++-渗透性离子通道是在三叉神经（TG）感觉神经元，角质形成细胞和肥大细胞中的表达和功能两者都被TG感觉神经元，头脸皮肤和脑膜支配。我的主要目标是定义TRPV4 非神经元细胞的依赖机制，特别是皮肤角质形成细胞和脑膜肥大细胞，以及如何这些可以调节偏头痛疼痛的三叉神经元神经元。一个特殊的有趣和理解偏头痛和其他病理疼痛的特征是痛苦的种族差异，在非洲人中被认为更为严重美国人。理性理解的障碍只是缺乏机械研究来阐明这一点现象。基于我的初步实验，即TRPV4通道对UVB敏感更加敏感在非裔美国人的皮肤角质形成细胞中，我也打算阐明赛车差异在角膜细胞和肥大细胞中取决于TRPV4的最前沿三叉疼痛信号传导。我的中央假设是皮肤角质形成细胞和脑膜肥大细胞中TRPV4通道的超敏反应有助于偏头痛炎症性疼痛的发展和永续存在，这一法规是由种族背景调节。为了检验这一假设，我提出了两个目的：1）确定炎症的方式改变角质形成细胞中的TRPV4通道灵敏度以及皮肤色素沉着如何确定通道的敏感性灵敏度； 2）表征偏头痛疼痛中肥大细胞中TRPV4的贡献。该提议的产量将填补明显的空白，以了解TRPV4如何促进角质形成细胞和肥大细胞的串扰 TG神经元支配它们并有助于偏头痛的病理生理。解构这些过程将为确定肥大细胞和角质形成细胞强大的促炎/pro- algeic有机功能。拟议的寻求对生物信号的可识别种族差异的追求受到询问的细胞谱系将使我们将这些发现用于个性化医学。在我的导师团队的指导下，其专家在相关研究领域的范围相关对于这个建议，以及我已经有效合作的建议，我建议有效地培训我的进一步培训职业发展。我希望：1）获得合作和团队组成的经验，2）扩大我的技能 - 基于实验室技术的平台，例如建模动物行为和肥大细胞细胞和分子测定，3）获取并将提前统计分析技能应用于我的研究，4）扩大我的沟通技巧，包括科学写作和演讲，并建立在我现有的管理集中和领导能力。拟议的培训将使我拥有独特的一组技能基于实验室的独立研究者，用于研究炎症性疼痛的多学科方法。