Skin Neuroimmune Mechanisms of Urticarial Itch

荨麻疹瘙痒的皮肤神经免疫机制

• 批准号: 10525850
• 负责人: AARON VER HEUL
• 金额: $ 14.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525850
• 关键词: Advisory Committees; Affect; Afferent Neurons; Agonist; Allergens; Allergic Disease; Allergic inflammation; Antihistamines; Atopic Dermatitis; Automobile Driving; Award; Behavior; Biological Assay; Biological Models; Biology; Biopsy; Cell physiology; Cells; Chronic; Clinical; Communities; Complement; Data; Disease; Doctor of Philosophy; Economic Burden; Epithelial; Exposure to; Family member; Fibrinogen; Funding; G-Protein-Coupled Receptors; Gene Expression; Genetic Polymorphism; Genomics; Goals; Histamine; Human; Hypersensitivity; IgE; Immune; Immune response; Immunoglobulins; Immunology; Impairment; In Vitro; Inflammatory; Interleukin-1; Interleukins; Kinetics; Knockout Mice; Laboratories; Mediating; Mediator of activation protein; Mentors; Microscopy; Mus; Neuroimmunomodulation; Neurons; Neuropeptides; Neurosciences; Orthologous Gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Play; Population; Postdoctoral Fellow; Pruritus; Publishing; Quality of life; Records; Recurrence; Research; Research Personnel; Resources; Role; Sampling; Scientist; Severities; Signal Transduction; Skin; Symptoms; Technical Expertise; Testing; Tissues; Training; Universities; Urticaria; Variant; Virulence Factors; Vocational Guidance; Washington; Work; Writing; anti-IgE; crosslink; cytokine; disabling symptom; effective therapy; functional genomics; humanized mouse; in vitro Assay; in vivo; insight; instructor; interest; mast cell; mouse model; neuroimmunology; novel; novel therapeutics; persistent symptom; promoter; response; single-cell RNA sequencing; skills; small molecule; translational model; two photon microscopy

PROJECT SUMMARY This proposal defines a 5-year plan to prepare Aaron Ver Heul, MD, PhD, to reach his long-term goal of independence as a physician-scientist studying the neuroimmunology of allergic diseases. He is currently an Instructor in the Division of Allergy and Immunology at Washington University doing post-doctoral studies in the laboratory of Dr. Brian Kim. There, Dr. Ver Heul has studied basic mechanisms of itch to complement his clinical interest in chronic spontaneous urticaria (CSU), an itchy skin condition characterized by exaggerated mast cell (MC) responses. He has demonstrated that the cytokine interleukin (IL)-33 enhances itch in a MC-dependent manner and proposes to extend these studies to CSU. Thus, the primary scientific goal of this proposal is to understand the role of IL-33 in CSU and itch. Washington University is an ideal place to perform the proposed training and research, with outstanding resources and expertise readily available. Dr. Brian Kim, the primary mentor, is an expert in neuroimmunology, atopic dermatitis, and itch. Dr. Steve Brody, the co-mentor, is an expert in translational models of epithelial biology. Both have strong records of continuous funding and training successful scientists. Dr. Ver Heul has also assembled an advisory committee with expertise in immunology, neuroscience, functional genomics, and in vivo microscopy, who will provide crucial scientific training and career guidance. He will take didactics in genomics, microscopy, and scientific writing. He will have multiple opportunities to present his work locally and to the larger scientific community. Dr. Ver Heul’s immediate objectives during the award period are to acquire requisite skills to complete the proposed research, publish the results, and successfully obtain independent funding. IL-33 is increased in a variety of allergic diseases including CSU, which affects 1% of the population. MCs are highly responsive to IL-33, and exaggerated MC activation is a major contributor to CSU pathogenesis. Recently, two distinct pathways by which MCs can be activated to cause itch were identified. One responds to allergens, while the other responds to a variety of small molecules including neuropeptides and many common drugs (known as basic secretagogues). Taken together with the demonstration that IL-33 enhances histaminergic itch, Dr. Ver Heul now proposes to test the hypothesis that IL-33 broadly amplifies different forms of MC-mediated itch responses. By completing the proposed aims, Dr. Ver Heul will define 1) how IL-33 enhances allergen- mediated itch and 2) how IL-33 enhances basic secretagogue-mediated itch. The proposed studies determine mechanisms of IL-33-enhanced MC activation in vitro and in mouse models of itch and extend these findings to analyses of CSU patient samples. Fulfilling the aims will provide new insight into mechanisms of CSU and itch and establish Dr. Ver Heul as an independent investigator in allergy and immunology.

项目概要 该提案制定了一个 5 年计划，旨在帮助医学博士 Aaron Ver Heul 做好准备，以实现他的长期目标： 独立作为研究过敏性疾病神经免疫学的医师科学家。他目前是一名 华盛顿大学过敏与免疫学系讲师，从事博士后研究 Brian Kim 博士的实验室。在那里，Ver Heul 博士研究了瘙痒的基本机制，以补充他的临床研究 对慢性自发性荨麻疹 (CSU) 感兴趣，这是一种以肥大细胞增多为特征的皮肤瘙痒症 （MC）回应。他证明细胞因子白细胞介素 (IL)-33 可以增强 MC 依赖性瘙痒 方式并建议将这些研究扩展到科罗拉多州立大学。因此，该提案的主要科学目标是 了解 IL-33 在 CSU 和瘙痒中的作用。 华盛顿大学是进行拟议培训和研究的理想场所，拥有杰出的 资源和专业知识随时可用。首席导师Brian Kim博士是神经免疫学专家， 特应性皮炎和瘙痒。联合导师Steve Brody博士是上皮细胞转化模型专家 生物学。两者都拥有持续资助和培训成功科学家的良好记录。 Ver Heul 博士还 组建了一个具有免疫学、神经科学、功能基因组学和体内专业知识的咨询委员会 显微镜，他们将提供重要的科学培训和职业指导。他将接受基因组学教学， 显微镜和科学写作。他将有多次机会在当地和更大范围内展示他的作品 科学界。 Ver Heul 博士在获奖期间的近期目标是获得必要的技能 完成拟议的研究，发表结果，并成功获得独立资助。 IL-33 在多种过敏性疾病中升高，包括影响 1% 人口的 CSU。 MC 是 对 IL-33 高度敏感，过度的 MC 激活是 CSU 发病的主要原因。最近， 确定了 MC 被激活引起瘙痒的两种不同途径。一个人会对过敏原做出反应， 而另一个则对各种小分子做出反应，包括神经肽和许多常见药物 （称为基本促分泌素）。结合 IL-33 增强组胺能瘙痒的证明， Ver Heul 博士现在提议检验 IL-33 广泛放大不同形式的 MC 介导的假设 痒反应。通过完成拟议的目标，Ver Heul 博士将定义 1) IL-33 如何增强过敏原- 介导的瘙痒；2) IL-33 如何增强基本促分泌素介导的瘙痒。拟议的研究确定 体外和小鼠瘙痒模型中 IL-33 增强 MC 激活的机制，并将这些发现扩展到 科罗拉多州立大学患者样本分析。实现这些目标将为 CSU 和痒的机制提供新的见解 并任命 Ver Heul 博士为过敏和免疫学领域的独立研究者。