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

• 批准号: 10676917
• 负责人: Hongzhen Hu
• 金额: --
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676917
• 关键词: Ablation; Acute; Affect; Afferent Neurons; Allergic; Allergic Contact Dermatitis; Animal Model; Applications Grants; Atopic Dermatitis; Automobile Driving; Binding; C Fiber; Cells; Chemicals; Chronic; Clinical; Code; Conscious; Cutaneous; Data; Development; Dryness; 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; 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

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.

概括 瘙痒被描述为一种令人不愉快的感觉，会引起抓挠的欲望。虽然急性抓伤是 清除皮肤刺激物的保护机制，慢性瘙痒会使人衰弱。另外，慢性瘙痒是 由于缺乏对潜在机制的了解，该病广泛存在且非常难以治疗。 因此，更好地了解慢性瘙痒的细胞和分子基础至关重要 开发新颖有效的疗法。尽管过去几十年来在解决问题方面取得了巨大进展 膜结合 G 蛋白偶联受体和离子通道的作用，特别是瞬时受体 初级感觉神经元和脊髓水平产生瘙痒感的潜在（TRP）通道 关于皮肤中的细胞和分子如何促进生产和生产，仍然有很多未知之处。 除了通过肥大细胞介导过敏性瘙痒之外，还可以调节慢性瘙痒。 初步研究表明，皮肤特异性敲除 Piezo2 严重减少了自发抓伤 多种慢性瘙痒小鼠模型。此外，小鼠自发瘙痒的减少 实验性干性皮肤与 TRPV1- 介导的机械诱发 C 纤维放电的丧失相关。 正 C 机械感受器。因此，我们假设 Piezo2-Merkel 细胞信号传导是 通过驱动TRPV1阳性C-在慢性瘙痒条件下产生自发瘙痒 慢性瘙痒条件下的机械感受器。在此拨款提案中，我们将：1）使用独特的遗传 研究机械敏感 Piezo2 通道和机械感觉的体内功能的方法 默克尔细胞介导自发瘙痒三种成熟的慢性瘙痒小鼠模型； 2） 证明默克尔细胞和瘙痒性 C 型机械感受器之间发生错误接线，以 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 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 Piezo2 通道和默克尔的总体理解做出重大贡献 细胞影响皮肤中的瘙痒信号，无疑会带来治疗慢性瘙痒的新治疗方法 痒。