HISTAMINE-INDEPENDENT MAST CELL NERVE INTERACTIONS IN ALLERGY

过敏中不依赖组胺的肥大细胞神经相互作用

• 批准号: 9160145
• 负责人: Qin Liu
• 金额: $ 38.13万
• 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: 2016-05-12 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160145
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; Afferent Neurons; Allergic; Allergic Conjunctivitis; Allergic Disease; Antihistamines; Axon; Behavioral; Calcium; Cell Degranulation; Cells; Chronic; Clinical; Clinical Treatment; Communication; Cyclosporine; Data; Development; Drug Targeting; Eczema; Family; Fiber; G-Protein-Coupled Receptors; GPR3 gene; Generations; Genes; Genetic; Histamine; Human; Hypersensitivity; Image; Imaging Techniques; Immunosuppressive Agents; Knowledge; Ligands; Mediating; Molecular; Molecular Genetics; Mus; Nerve; Neuraxis; Neurodermatitis; Neurons; Opioid; Pain; Pathogenesis; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Physiological; Play; Prevention therapy; Productivity; Quality of life; Refractory; Role; Sensory; Signal Transduction; Skin; Specificity; Spinal Cord; Spinal Ganglia; Structure of trigeminal ganglion; Symptoms; Testing; Therapeutic; Tissue membrane; Transgenic Mice; Translating; Urticaria; base; behavioral response; behavioral study; human subject; in vivo; innovation; mast cell; neuropeptide FF; novel; novel therapeutic intervention; prevent; receptor; reconstitution; relating to nervous system; research study

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.

瘙痒是许多过敏性疾病的主要症状，严重影响生活质量和 位于三叉神经节和背根神经节（DRG）的初级感觉神经元发挥着重要作用。 这些神经元在过敏性瘙痒的产生中发挥重要作用。 （瘙痒原）通过皮肤或粘膜组织中外周轴突上的一组瘙痒受体， 并通过其中央轴突将信号传输到脊髓，这与经过充分研究的组胺不同。 通路，过敏性瘙痒中与组胺无关的瘙痒通路此前我们尚未明确。 我们发现，G 蛋白偶联受体大家族中的几种新型瘙痒受体称为 Mrgprs。 一些 Mrgprs 识别不同的瘙痒原，并介导不依赖组胺的瘙痒。 表明 Mrgprs 是肥大细胞介导的过敏性瘙痒所必需的。该提案旨在揭示肥大细胞介导的过敏性瘙痒。 我们将测试 Mrgprs 是否介导肥大细胞和原代细胞之间的相互作用。 目标 1 中使用分子、遗传和成像方法研究过敏性瘙痒中的感觉纤维。此外，我们将 在目标 2 中鉴定肥大细胞脱粒后释放的内源性 Mrgpr 配体。在目标 3 中，我们寻求 将我们的发现从小鼠转移到人类身上并不能与人类形成明确的直系同源对。 因此，根据我们的初步数据，它们在瘙痒中的作用尚不清楚。 人类 MrgprX1 介导对肥大细胞介导的过敏的神经和行为反应，将进行测试 目标 3。这些研究将揭示过敏性瘙痒的神经基础，并对 既是瘙痒发病机制的研究，又是瘙痒的临床治疗。