Functional Characterization and Sensitization of Human Pruriceptors

人类瘙痒感受器的功能特征和敏感性

• 批准号: 9035997
• 负责人: Steve Davidson
• 金额: $ 21.17万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035997
• 关键词: Afferent Neurons; Analgesics; Anatomy; Animal Model; Animals; Antihistamines; Atopic Dermatitis; Axon; Calcium; Cations; Chronic; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Controlled Study; Coupling; Culture Techniques; Data; Dermatology; Development; Drug Design; Electrophysiology (science); Exposure to; Fiber; Future; GTP-Binding Proteins; Gene Expression; Gene Expression Profile; Genetic Markers; Goals; Growth; Heterogeneity; Histamine; Human; Human Biology; Image; In Vitro; Individual; Ion Channel; Knowledge; Light; Mediating; Medicine; Membrane; Methods; Microfluidics; Modeling; Monitor; Moral Obligations; Mus; Neural Pathways; Neurons; Outcome; Pain; Patients; Peripheral; Pharmacology; Physiological; Physiology; Primates; Process; Proteins; Protocols documentation; Pruritus; Quality of life; RNA; Receptor Activation; Research; Risk; Rodent; Rodent Model; Role; Scientist; Sensory Physiology; Signal Transduction; Skin; Spinal Ganglia; Staging; Stimulus; TSLP gene; Testing; Toll-like receptors; Translations; Validation; Visit; Work; axon growth; base; chronic itch; experience; gene product; improved; innovation; keratinocyte; mRNA Expression; meetings; neuronal cell body; novel; novel strategies; patch clamp; pre-clinical; preclinical study; public health relevance; receptor; receptor coupling; receptor function; research study; response; skin disorder; somatosensory; success; therapeutic target

 DESCRIPTION (provided by applicant) The relief of chronic itch (pruritus) would improve the quality of life of tens of millions of people in the US. Pruritus is poorly controlled by antihistamines but histamine-independent receptors have only recently been identified as potential targets for anti-pruritics. These newly identified pruritic receptors include the Mas-related G protein receptors, Toll-like receptors, and the thymic stromal lymphopoietin receptor, and have been found in different subsets of rodent sensory neurons. Presently, the localization and signaling mechanisms of homologous itch receptors in human sensory neurons are unknown, creating potential obstacles for translation. For this proposal we have developed a novel strategy to establish target validity at a preclinical stage by performing physiological studies in viable human sensory neurons in vitro. The major objectives of this proposal are to 1) understand the transduction of histaminergic and non-histaminergic itch stimuli in characterized human sensory neurons, and 2) to determine whether keratinocytes obtained from donors with atopic dermatitis control sensitization of pruriceptive neurons. Human sensory neurons will be characterized based on functional responses to pruritogens and on gene expression profile. Pruritic receptors have been shown to couple functionally and selectively to Transient Receptor Potential (TRP) channels in rodents. We will test whether human TRP channels are likewise gated by pruritic receptor activation in human sensory neurons and will examine whether other classes of ion channels couple to human pruritic receptors. In Aim 2 our goal is to understand sensitization of pruriceptive sensory neurons, a phenomenon that can explain the ongoing and heightened itch experienced by individuals with chronic pruritic conditions including atopic dermatitis. We hypothesize that atopic human keratinocytes will control pruritic receptor function and excitability of human sensory neurons. For this aim we develop novel human sensory neurons and human keratinocytes co-culture techniques. Our proposal represents the first steps toward a broader implementation of in vitro human sensory physiology. This strategy will provide valuable preclinical assessment on the feasibility of targeting novel receptors in human for itch and pain, and reduce the risks involved in clinical trials.

 描述（由申请人提供）缓解慢性瘙痒（瘙痒症）将改善美国数千万人的生活质量。抗组胺药对瘙痒控制不佳，但组胺非依赖性受体最近才被确定为抗瘙痒药的潜在靶点。这些新发现的受体包括Mas相关的G蛋白受体、Toll样受体和胸腺基质淋巴细胞生成素受体，并且已经在啮齿动物感觉神经元的不同亚群中发现。目前，人类感觉神经元中同源瘙痒受体的定位和信号机制尚不清楚，这给翻译带来了潜在的障碍。对于这一建议，我们已经开发了一种新的策略，建立目标的有效性在临床前阶段进行生理学研究，在活的人类感觉神经元在体外。本提案的主要目的是1）了解组胺能和非组胺能瘙痒刺激在特征性人感觉神经元中的转导，和2）确定从患有特应性皮炎的供体获得的角质形成细胞是否控制刺激感受神经元的致敏。人类感觉神经元将基于对促神经生长剂的功能反应和基因表达谱来表征。瘙痒受体已显示在啮齿动物中功能性和选择性地偶联至瞬时受体电位（TRP）通道。我们将测试人类TRP通道是否同样通过人类感觉神经元中的多巴胺受体激活来门控，并将检查其他类型的离子通道是否与人类多巴胺受体偶联。在目标2中，我们的目标是了解伤害性感觉神经元的致敏作用，这种现象可以解释患有慢性过敏性疾病（包括特应性皮炎）的个体所经历的持续和加剧的瘙痒。我们推测，特应性人类角质形成细胞将控制过敏性受体的功能和人类感觉神经元的兴奋性。为此，我们开发了新的人类感觉神经元和人类角质形成细胞共培养技术。我们的提议代表了更广泛地实施体外人类感觉生理学的第一步。这一策略将为靶向治疗人类瘙痒和疼痛的新型受体的可行性提供有价值的临床前评估，并降低临床试验的风险。