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: 9272358
• 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/9272358
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; Afferent Neurons; Allergic; Allergic Conjunctivitis; Allergic Disease; Antihistamines; Axon; Behavioral; Calcium; Cell Degranulation; Chronic; Clinical; Clinical Treatment; Communication; Cyclosporine; Data; Development; Drug Targeting; Eczema; Family; Fiber; G-Protein-Coupled Receptors; Generations; Genes; Genetic; Histamine; Human; Hypersensitivity; Imaging Techniques; Immunosuppressive Agents; Knowledge; Ligands; Mediating; Molecular; Molecular Genetics; Mus; Neuraxis; Neurodermatitis; Neurons; Opioid; Pain; Pathogenesis; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Prevention; Productivity; Pruritus; 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; experimental study; genetic approach; human subject; imaging approach; in vivo; innovation; mast cell; neuropeptide FF; novel; novel therapeutic intervention; prevent; receptor; reconstitution; relating to nervous system

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， 生产力位于三叉神经节和背根神经节（DRG）的初级感觉神经元起着重要的作用。 在过敏性瘙痒的产生中起重要作用。这些神经元检测内源性瘙痒诱导分子 通过皮肤或粘膜组织中其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。与研究充分的组胺相反， 尽管组胺非依赖性瘙痒通路在过敏性瘙痒中的作用尚不明确。此前，我们发现 G蛋白偶联受体大家族中的几种新的瘙痒受体，称为Mrkidney。我们发现 几种Mrsal识别不同的致敏原，并介导组胺非依赖性瘙痒。我们的最新结果 表明肥大细胞介导过敏性瘙痒需要Mrs12。这项提案旨在揭示 基本机制。我们将测试Mrs12是否介导肥大细胞和原发性肥大细胞之间的相互作用。 过敏性瘙痒中的感觉纤维使用分子，遗传和成像方法在目的1中。此外，我们将 鉴定Aim 2中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化为人类。人类的精子不能与 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MrgprX 1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 目标3。这些研究将揭示过敏性瘙痒的神经基础，并将对 无论是瘙痒发病机制的研究，还是瘙痒的临床治疗。