The molecular basis of Interleukin-31 driven itch

Interleukin-31 驱动瘙痒的分子基础

基本信息

项目摘要

PROJECT SUMMARY Chronic itch is a symptom of many many diseases and causes stress, loss of sleep, and a decline in quality of life. In addition to the psychological damage, constant scratching physically exacerbates skin disease by enhancing skin inflammation and promoting infection. However, the only specific treatment options are antihistamines, which mostly are ineffective. Recently, the cytokine IL-31 was identified as a new target for itch. A newly-completed Phase II clinical trial of an antibody targeting the IL-31 receptor (IL31RA) showed remarkable efficacy in reducing itch in atopic dermatitis patients. IL-31 has been proposed to act by stimulating a subset of neurons in the skin that specifically transmits itch signals, and which is characterized in mice by expression of a protein called MAS-related G protein- coupled receptor A3 (Mrgpra3). However, while we have confirmed that Il31ra-positive neurons do exist, they do not overlap with Mrgpra3-positive neurons. However, Mrgprs may be involved indirectly, as we have preliminary evidence that IL-31 induces keratinocytes to release Mrgpr-activating substances. Thus, we hypothesize that IL-31 induces itch directly by acting on a new, uncharacterized subset of neurons, and indirectly by inducing keratinocytes to produce Mrgpr- activating pruritogens. We propose three sets of experiments to test our hypothesis. First, we will evaluate whether IL-31 induces changes in excitability and/or transcriptional programming in IL31RA-positive neurons. This could lead to long-term, persistent increases in itch sensation that may even outlast exposure to IL-31. Second, we will determine whether the substances released by keratinocytes that activate Mrgprs are members of a newly-identified class of Mrgpr ligands. We also will examine IL-31-induced itch in Mrgpr knockout mice. Third, we will determine the relative contributions of IL31RA-positive neurons and keratinocytes in IL-31-induced itch by knocking out IL31RA specifically in neurons or in epithelial cells. These will inform future research directions and may help to select drug delivery options. The data generated from our proposed experiments will have direct applications in the clinic, as the first specific anti-pruritic treatment option since antihistamines is an anti-IL31RA antibody. An understanding of how IL-31 works is essential to interpret future clinical results, to predict who will and will not benefit from anti-IL31RA therapy, to develop even more specific treatment options, and to identify other diseases that might be treated by targeting IL-31.
项目概要 慢性瘙痒是许多疾病的症状,会导致压力、睡眠不足和睡眠质量下降 生活。除了心理上的伤害外,经常抓挠身体也会加剧皮肤病 增强皮肤炎症并促进感染。然而,唯一的具体治疗选择是 抗组胺药,大多无效。最近,细胞因子IL-31被确定为瘙痒的新靶标。 新完成的针对IL-31受体(IL31RA)的抗体的II期临床试验显示出显着的效果 具有减轻特应性皮炎患者瘙痒的功效。 IL-31 已被提议通过刺激一部分 皮肤中专门传递瘙痒信号的神经元,其特征是在小鼠中表达 称为 MAS 相关 G 蛋白偶联受体 A3 (Mrgpra3) 的蛋白质。然而,虽然我们已经确认 Il31ra 阳性神经元确实存在,它们与 Mrgpra3 阳性神经元不重叠。然而,Mrgprs 可能是 间接参与,因为我们有初步证据表明 IL-31 诱导角质形成细胞释放 Mrgpr 激活剂 物质。因此,我们假设 IL-31 通过作用于一个新的、未表征的子集而直接诱发瘙痒。 神经元,并间接通过诱导角质形成细胞产生 Mrgpr 激活瘙痒剂。我们提出三个 一组实验来检验我们的假设。首先,我们将评估 IL-31 是否会引起兴奋性变化 和/或 IL31RA 阳性神经元中的转录编程。这可能会导致长期、持续的 瘙痒感增加,甚至可能比接触 IL-31 更持久。其次,我们将确定是否 角质形成细胞释放的激活 Mrgprs 的物质是新鉴定的 Mrgpr 类别的成员 配体。我们还将在 Mrgpr 敲除小鼠中检查 IL-31 诱导的瘙痒。第三,我们要确定相对关系 通过敲除 IL31RA,IL31RA 阳性神经元和角质形成细胞在 IL-31 诱导的瘙痒中的作用 特别是在神经元或上皮细胞中。这些将为未来的研究方向提供信息,并可能有助于选择 药物输送选项。我们提出的实验产生的数据将直接应用于 由于抗组胺药是一种抗 IL31RA 抗体,因此作为第一个特异性抗瘙痒治疗选择。一个 了解 IL-31 的工作原理对于解释未来的临床结果、预测谁会或不会发挥作用至关重要 受益于抗 IL31RA 治疗,开发更具体的治疗方案,并识别其他疾病 可以通过靶向 IL-31 来治疗。

项目成果

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Benjamin Dwight-Clyde McNeil其他文献

Benjamin Dwight-Clyde McNeil的其他文献

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{{ truncateString('Benjamin Dwight-Clyde McNeil', 18)}}的其他基金

The molecular basis of Interleukin-31 driven itch
Interleukin-31 驱动瘙痒的分子基础
  • 批准号:
    10113543
  • 财政年份:
    2019
  • 资助金额:
    $ 34.08万
  • 项目类别:
The molecular basis of Interleukin-31 driven itch
Interleukin-31 驱动瘙痒的分子基础
  • 批准号:
    10352216
  • 财政年份:
    2019
  • 资助金额:
    $ 34.08万
  • 项目类别:
The molecular basis of Interleukin-31 driven itch
Interleukin-31 驱动瘙痒的分子基础
  • 批准号:
    9899207
  • 财政年份:
    2019
  • 资助金额:
    $ 34.08万
  • 项目类别:

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