Immune Regulation of Atopic Itch

特应性瘙痒的免疫调节

• 批准号: 9326912
• 负责人: Brian Kim
• 金额: $ 33.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326912
• 关键词: Address; Adult; Affect; Afferent Neurons; Atopic Dermatitis; Behavior; Biological Assay; Cells; Child; Chloroquine; Chronic; Clinical; Cytokine Signaling; Data; Development; Disease; Economic Burden; G-Protein-Coupled Receptors; Histamine; Human; Image; Immune; Immune system; Immunologics; Individual; Inflammation; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Interleukins; Janus kinase; Janus kinase 1; Knockout Mice; Lead; Lesion; Lymphoid Cell; Measures; Mediating; Mediator of activation protein; Mus; Nerve Fibers; Nervous system structure; Neurons; Orthologous Gene; Pathogenesis; Pathway interactions; Patients; Prevalence; Production; Pruritus; Public Health; RNA; Rag1 Mouse; Relapse; Role; Sensory; Serotonin; Severities; Severity of illness; Signal Transduction; Skin; T-Lymphocyte; Testing; Th2 Cells; Time; Transcript; afferent nerve; cell type; chronic itch; cytokine; disabling symptom; immunoregulation; improved; in vivo; kinase inhibitor; neurophysiology; novel therapeutics; response; skin disorder; small molecule; synergism; translational approach; treatment strategy

PROJECT SUMMARY/ABSTRACT Atopic dermatitis (AD) is a chronic, relapsing skin disease that affects children and adults. This disease is a growing public health problem and a large economic burden worldwide. The central and most debilitating symptom in AD is chronic itch. While some patients can be treated successfully with existing therapies, there is a continuing need for the development of new therapies to treat patients who do not respond to current AD treatment strategies. We and others have shown that the production of the type 2 cytokines interleukin (IL)-4 and IL-13 by T helper type 2 (TH2) cells and newly identified group 2 innate lymphoid cells (ILC2s) contribute to AD pathogenesis. Preliminary studies have also shown that the receptors for IL-4 and IL- 13 are highly expressed on itch-sensing primary sensory neurons. However, the precise role of TH2 cells, ILC2s and type 2 cytokines in mediating AD-associated itch remains poorly defined. Further, type 2 cytokines are known to be dependent on Janus kinase (JAK) signaling in immune cells for their effector functions. However, whether JAK signaling in primary sensory neurons elicits itch remains unknown. The central hypothesis of this proposal is that atopic itch arises from interactions between type 2 immune cells and primary sensory neurons via JAK signaling. To test this, in Specific Aim 1 we will employ genetically modified TH2 cell- and/or ILC2-deficient mice to investigate the role of these immune cells and their associated cytokines in evoking neuronal excitation and itch behavior. In Specific Aim 2, we will employ Cre-dependent conditional knockout mice in which Jak1 is selectively deleted from immune cells or primary sensory neurons to determine whether sensory neuron-specific JAK signaling mediates pruritogen-elicited neuronal activation and itch responses. We anticipate that gaining a better understanding of the immunologic pathways that interact with the primary pruriceptors to promote itch in the context of AD could lead to new anti-itch therapies.

项目总结/摘要 特应性皮炎（AD）是一种慢性复发性皮肤病，影响儿童和成人。这种疾病是一种 日益严重的公共卫生问题和巨大的经济负担。最重要的也是最让人虚弱的 AD症状是慢性瘙痒。虽然有些患者可以用现有的治疗方法成功治疗， 持续需要开发新的疗法来治疗对化疗无反应的患者， 目前的AD治疗策略。我们和其他人已经表明，2型细胞因子的产生 T辅助2型（TH 2）细胞和新鉴定的第2组先天性淋巴样细胞产生的白细胞介素（IL）-4和IL-13 ILC 2参与AD的发病机制。初步研究还表明，IL-4和IL-10的受体可能与IL-10的表达有关。 13在感觉瘙痒的初级感觉神经元上高度表达。然而，TH 2细胞的确切作用， ILC 2和2型细胞因子在介导AD相关瘙痒中的作用仍不明确。此外，2型细胞因子 已知其效应子功能依赖于免疫细胞中的Janus激酶（JAK）信号传导。 然而，初级感觉神经元中的JAK信号是否诱发瘙痒仍然未知。中央 该建议的假设是特应性瘙痒是由2型免疫细胞之间的相互作用引起的 和初级感觉神经元之间的联系。为了验证这一点，在具体目标1中，我们将采用遗传学方法， 修饰的TH 2细胞和/或ILC 2缺陷小鼠，以研究这些免疫细胞及其相关的 引起神经元兴奋和瘙痒行为的细胞因子。在具体目标2中，我们将使用依赖于Cr的 从免疫细胞或初级感觉神经元中选择性删除Jak 1的条件性敲除小鼠 为了确定感觉神经元特异性JAK信号传导是否介导促纤维素原引起的神经元活化， 和瘙痒反应。我们预计，更好地了解免疫途径， 在AD的背景下，与主要的瘙痒感受器相互作用以促进瘙痒可能导致新的止痒剂， 治疗