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Deciphering the Piezo2-Merkel cell signaling mechanisms in itch

破译瘙痒中的 Piezo2-Merkel 细胞信号传导机制

基本信息

批准号：
10454374
负责人：
Hongzhen Hu
金额：
$ 52.39万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454374
关键词：
Ablation Acute Affect Afferent Neurons Allergic Allergic Contact Dermatitis Animal Model Applications Grants Atopic Dermatitis Automobile Driving C Fiber Cells Chemicals Chronic Clinical Code Conscious Cutaneous Data Development Esthesia Experimental Models Fiber G-Protein-Coupled Receptors General Population Generations Genetic Goals Human Ion Channel Knock-out Lead Light Mechanical Stimulation Mechanics Mechanoreceptors Mediating Mediation Mediator of activation protein Membrane Merkel Cells Modality Modeling Molecular Mus Neurons Pathogenesis Patients Pattern Piezo 2 ion channel Pilot Projects Play Population Process Production Productivity Pruritus Quality of life Regulation Role Self-Injurious Behavior Sensory Signal Transduction Skin Spinal Cord TRP channel TRPV1 gene Testing Topical application chronic itch conditional knockout cytokine effective therapy genetic approach in vivo mast cell mechanical force mechanical stimulus mouse model new therapeutic target novel therapeutic intervention novel therapeutics optogenetics skin disorder skin irritant somatosensory tissue injury

项目摘要

SUMMARY Itch is described as an unpleasant sensation that elicits the desire to scratch. Although acute scratching is the protective mechanism to remove irritants from the skin, chronic itch is debilitating. In addition, chronic itch is widespread and very difficult to treat because of a lack of understanding of the underlying mechanisms. Therefore, it is critical to gain a better understanding of the cellular and molecular basis of chronic itch toward the development of novel and effective therapies. Despite great progress in the past few decades in unraveling the role of membrane bound G-protein coupled receptors and ion channels, especially transient receptor potential (TRP) channels in the generation of itch sensation at the levels of primary sensory neurons and spinal cord, much remains unknown about how the cells and molecules in the skin contribute to the production and regulation of chronic itch other than the mediation of allergic itch by mast cells. Pilot studies showed that skin-specific knockout of Piezo2 severely reduced the spontaneous scratching in multiple mouse models of chronic itch. Moreover, the reduction of spontaneous itch in mice subjected to experimental dry skin is correlated with a loss of mechanically evoked C-fiber firing mediated by the TRPV1- positive C-mechanoreceptors. We thus hypothesized that Piezo2-Merkel cell signaling is required for the generation of spontaneous itch under chronic itch conditions by driving the TRPV1-positive C- mechanoreceptors under chronic itch conditions. In this grant proposal we will: 1) Use unique genetic approaches to investigate in vivo functions of the mechanosensitive Piezo2 channels and mechanosensory Merkel cells in mediating spontaneous itch three well-established mouse models of chronic itch; 2) Demonstrate that miswiring occurs between the Merkel cells and the pruriceptive C-type mechanoreceptor to promote spontaneous itch in chronic itch mice, thereby providing the cellular and molecular basis for chronic itch in multiple mouse models of chronic itch. Our findings will provide a major contribution to our general understanding of how Piezo2 channels and Merkel cells affect itch signaling in the skin, and undoubtedly lead to new therapeutic approaches for treating chronic itch.

总结痒被描述为一种令人不快的感觉，这种感觉会激发抓挠的欲望。虽然急性抓挠是保护机制，以消除刺激物从皮肤，慢性瘙痒是衰弱。此外，慢性瘙痒是由于缺乏对潜在机制的了解，这种疾病广泛存在且很难治疗。因此，更好地了解慢性瘙痒的细胞和分子基础对于新的和有效的治疗方法的发展。尽管在过去几十年里，膜结合G蛋白偶联受体和离子通道，特别是瞬时受体在初级感觉神经元和脊髓神经元水平上，然而，关于皮肤中的细胞和分子如何促进产生和调节慢性瘙痒，而不是通过肥大细胞介导过敏性瘙痒。初步研究表明，皮肤特异性敲除Piezo 2严重减少了小鼠的自发抓挠，慢性瘙痒的多种小鼠模型。此外，在小鼠中，实验性皮肤干燥与TRPV 1介导的机械诱发C纤维放电的丧失相关。 C型机械感受器阳性。因此，我们假设Piezo 2-默克尔细胞信号传导是需要的，在慢性瘙痒条件下通过驱动TRPV 1阳性C- 慢性瘙痒条件下的机械感受器。在这项拨款提案中，我们将：1）使用独特的遗传研究机械敏感Piezo 2通道和机械敏感Piezo 2通道的体内功能的方法默克尔细胞介导自发性瘙痒三种建立良好的小鼠慢性瘙痒模型; 2）证明在默克尔细胞和伤害感受性C型机械感受器之间发生错误连接，促进慢性瘙痒小鼠的自发瘙痒，从而为慢性瘙痒提供细胞和分子基础。在多种慢性瘙痒小鼠模型中的瘙痒。我们的研究结果将为我们对Piezo 2通道和默克尔细胞影响皮肤中的瘙痒信号，毫无疑问，这为治疗慢性瘙痒症提供了新的治疗方法。发痒.