Skin Neuroimmune Mechanisms of Urticarial Itch

项目摘要 该提案定义了一个5年计划，以准备Aaron Ver Heul，MD，PhD，以实现他的长期目标， 作为一名研究过敏性疾病神经免疫学的医生兼科学家的独立性。彼现为 华盛顿大学变态反应和免疫学系讲师，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 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瘙痒性皮肤病 (MC)应答他已经证明，细胞因子白细胞介素（IL）-33增强了MC依赖性瘙痒。 并建议将这些研究扩展到CSU。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。 华盛顿大学是一个理想的地方，执行拟议的培训和研究，与杰出的 资源和专业知识随时可用。布莱恩·金博士，主要的导师，是神经免疫学专家， 特应性皮炎和瘙痒。史蒂夫·布罗迪博士，共同导师，是上皮细胞转化模型的专家， 生物学两者都有持续资助和培训成功科学家的良好记录。Ver Heul博士还 组建了一个咨询委员会，拥有免疫学、神经科学、功能基因组学和体内 显微镜，谁将提供关键的科学培训和职业指导。他将学习基因组学的教学法， 显微镜和科学写作。他将有多种机会在当地和更大的地方展示他的作品 科学界。Ver Heul博士在获奖期间的直接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在各种过敏性疾病中增加，包括影响1%人口的CSU。MC是 对IL-33高度反应和过度的MC活化是CSU发病机制的主要贡献者。最近， 鉴定了两种不同的途径，通过这两种途径MC可以被激活以引起瘙痒。一个对过敏原有反应， 而另一种则对包括神经肽和许多常见药物在内的各种小分子有反应 （称为基本促分泌素）。结合IL-33增强组胺能瘙痒的证明， 博士Ver Heul现在提出测试IL-33广泛扩增不同形式的MC介导的细胞增殖的假设。 瘙痒反应。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- 介导的瘙痒和2）IL-33如何增强基础促分泌素介导的瘙痒。拟议的研究确定 IL-33在体外和小鼠瘙痒模型中增强MC活化的机制，并将这些发现扩展到 CSU患者样本的分析。这些目标的实现将为CSU和瘙痒的机制提供新的见解 并将Ver Heul博士确立为过敏和免疫学的独立研究者。

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.