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: 10225638
• 负责人: Hongzhen Hu
• 金额: $ 49.42万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10225638
• 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; Stimulus; TRP channel; TRPV1 gene; Testing; Topical application; chronic itch; conditional knockout; cytokine; effective therapy; genetic approach; in vivo; mast cell; mechanical force; 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.

摘要 瘙痒被描述为一种令人不快的感觉，引起抓挠的欲望。虽然急性划痕是 保护机制去除皮肤上的刺激物，慢性瘙痒使人虚弱。此外，慢性瘙痒是 由于缺乏对潜在机制的了解，因此非常普遍且非常难以治疗。 因此，更好地了解慢性瘙痒的细胞和分子基础是至关重要的。 开发新颖有效的治疗方法。尽管在过去的几十年里在解体方面取得了巨大的进步 膜结合G蛋白偶联受体和离子通道，尤其是瞬时受体的作用 初级感觉神经元和脊髓水平的Trp通道在瘙痒感觉产生中的作用 关于皮肤中的细胞和分子如何参与生产和 除肥大细胞调节过敏性瘙痒外，对慢性瘙痒的调节。 初步研究表明，皮肤特异的Piezo2基因敲除严重减少了皮肤上的自发抓挠 多种慢性瘙痒小鼠模型。此外，对小鼠自发性瘙痒的减少 实验性皮肤干燥与TRPV1介导的机械诱发C纤维放电的丧失有关- C-机械感受器阳性。因此，我们假设Piezo2-Merkel细胞信号是 慢性瘙痒条件下自发性瘙痒的发生通过驱动TRPV1阳性的C- 慢性瘙痒条件下的机械感受器。在这份赠款提案中，我们将：1)使用独特的基因 机械敏感的Piezo2通道和机械感觉的体内功能研究进展 默克尔细胞在介导自发性瘙痒三种已建立的慢性瘙痒小鼠模型中的作用 证明默克尔细胞和瘙痒敏感的C型机械感受器之间发生错误连接 促进慢性瘙痒小鼠自发性瘙痒，从而为慢性瘙痒提供细胞和分子基础 多只小鼠慢性瘙痒模型。 我们的发现将为我们对Piezo2频道和默克尔如何 细胞影响皮肤中的瘙痒信号，无疑导致治疗慢性疾病的新的治疗方法。 很痒。