HISTAMINE-INDEPENDENT MAST CELL NERVE INTERACTIONS IN ALLERGY

瘙痒是许多过敏性疾病的主要症状，严重影响生活质量和 生产力。存在于三叉神经节和背根神经节的初级感觉神经元在 在过敏性瘙痒的产生中起着至关重要的作用。这些神经元检测内源性瘙痒诱导分子。 (瘙痒原)通过皮肤或粘膜组织外周轴突上的一组瘙痒受体， 并通过它们的中央轴突将信号传输到脊髓。与研究得很好的组胺相反 在过敏性瘙痒中，组胺非依赖性瘙痒通路仍未明确。此前，我们确定了 G蛋白偶联受体大家族中的几个新的瘙痒受体被称为MRGPR。我们发现 几个MRGPR识别不同的瘙痒原，并介导组胺非依赖性瘙痒。我们的最新结果 提示肥大细胞介导的过敏性瘙痒需要MRGPR。这项提案旨在揭示 潜在的机制。我们将测试mrgprs是否介导了肥大细胞和原代细胞之间的相互作用。 在目标1中使用分子、遗传和成像方法在过敏性瘙痒中的感觉纤维。此外，我们将 确定目标2中肥大细胞脱颗粒后释放的内源性MRGPR配体。在目标3中，我们寻求 将我们的发现从老鼠转移到人类身上。人类的MRGPR不会形成清晰的同源对 老鼠先生。因此，它们在瘙痒中的作用尚不清楚。根据我们的初步数据，我们假设 人类MRgprX1介导对肥大细胞介导的过敏的神经元和行为反应，这将进行测试 这些研究将揭示过敏性瘙痒的神经基础，并将对 瘙痒的发病机制研究和临床治疗。

Itch is a primary symptom of many allergic conditions, and severely affects the quality of life and productivity. Primary sensory neurons residing in the trigeminal ganglia and dorsal root ganglia (DRG) play an essential role in the generation of allergic itch. These neurons detect endogenous itch-inducing molecules (pruritogens) via a group of itch receptors on their peripheral axons in the skin or mucosal membrane tissues, and transmit signals to the spinal cord via their central axons. In contrast to the well-studied histamine pathway, histamine-independent itch pathways in allergic itch remain poorly defined. Previously, we identified several novel itch receptors within a large family of G-protein‒coupled receptors called Mrgprs. We found that several Mrgprs recognize distinct pruritogens, and mediate histamine-independent itch. Our latest results indicate that Mrgprs are required for mast cell-mediated allergic itch. This proposal aims to uncover the underlying mechanisms. We will test whether Mrgprs mediate the interaction between mast cells and primary sensory fibers in allergic itch using molecular, genetic and imaging approaches in Aim 1. Furthermore, we will identify the endogenous Mrgpr ligands released by mast cells upon degranulation in Aim 2. In Aim 3, we seek to translate our discoveries from mice to humans. Human Mrgprs do not form clear orthologous pairs with mouse Mrgprs. Their role in itch is therefore unclear. Based on our preliminary data, we hypothesize that human MrgprX1 mediates neuronal and behavioral response to mast cell-mediated allergy, which will be tested in Aim 3. These studies will reveal the neural basis underlying allergic itch and will have a significant impact on both the study of itch pathogenesis and the clinical treatment of itch.