Skin Neuroimmune Mechanisms of Urticarial Itch

项目总结 这项建议定义了一个5年计划，使Aaron Ver Heul，医学博士，达到他的长期目标 作为一名内科科学家，独立研究过敏性疾病的神经免疫学。他目前是一名 华盛顿大学过敏和免疫学系的讲师正在进行博士后研究 布莱恩·金博士的实验室。在那里，Ver Heul博士研究了瘙痒的基本机制，以补充他的临床 对慢性自发性荨麻疹(CSU)感兴趣，这是一种以肥大细胞为特征的瘙痒皮肤疾病 (MC)响应。他已经证明了细胞因子IL-33增强MC依赖型患者的瘙痒 并建议将这些研究扩展到基辅州立大学。因此，这项提议的主要科学目标是 了解IL-33在CSU和瘙痒中的作用。 华盛顿大学是进行拟议中的培训和研究的理想场所，拥有出色的 现成的资源和专业知识。主要导师布莱恩·金博士是神经免疫学专家， 特应性皮炎，还有瘙痒。共同导师史蒂夫·布罗迪博士是上皮细胞翻译模型方面的专家 生物学。这两家公司都有持续资助和培养成功科学家的良好记录。Ver Heul博士也有 组建了一个咨询委员会，具有免疫学、神经科学、功能基因组学和活体内的专业知识 他将提供至关重要的科学培训和职业指导。他将接受基因组学方面的教育， 显微镜和科学写作。他将有多个机会在当地和更大的地方展示他的作品 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，发布结果，并成功获得独立资金。 IL-33在包括CSU在内的各种过敏性疾病中增加，CSU影响1%的人口。MCS是 对IL-33高度敏感，过度激活MC是CSU发病的主要因素。最近， 通过两种不同的途径，MC可以被激活以引起瘙痒。一种是对过敏原有反应， 而另一个对包括神经肽和许多常见药物在内的各种小分子都有反应 (称为基本分泌物)。结合IL-33增强组胺能瘙痒的证明， Ver Heul博士现在建议测试这一假设，即IL-33广泛放大不同形式的MC介导的 瘙痒反应。通过完成提出的目标，Ver Heul博士将定义1)IL-33如何增强过敏原- 介导性瘙痒和2)IL-33如何增强基础促分泌剂介导性瘙痒。拟议的研究确定了 IL-33在体外和小鼠瘙痒模型中增强MC激活的机制，并将这些发现扩展到 CSU患者样本分析。实现这些目标将为CSU和瘙痒的发病机制提供新的见解 并将Ver Heul博士确立为过敏和免疫学领域的独立研究员。

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.