Elucidating the Role of Cutaneous Environmental Factors in the Development of Allergic Disease

项目摘要/摘要 这份提案描述了安娜·艾森斯坦博士职业发展的严格培训计划 作为一名独立科学家。首席研究员是一位内科科学家，他最近完成了 皮肤科实习医生。她的职业目标是成为一名独立的调查员，研究 皮肤屏障和免疫功能，尤其对过敏性疾病感兴趣。她提议扩大她的业务范围 在博士的共同指导下，通过深入的研究经验进行免疫学和过敏方面的培训。 安德鲁·王和约瑟夫·克拉夫特博士以及一个由顶尖科学家和 免疫学和皮肤科的内科科学家。除了出色的指导外，该提案还包括 严格的课程安排、研讨会和外部会议。这些有计划的活动将使她具备必要的 成为一名成功的独立调查员的技能。 这项建议的研究目的是了解为什么特应性皮炎(湿疹)患者 容易对食物过敏，这两种疾病的患病率都在呈指数级上升。初步数据显示， 环境异生物质，如常见的非处方药和食品防腐剂，会引起过敏 口服或局部使用时的佐剂。这些产品都被发现能激活外源生物 核因子红系相关因子受体(Nrf2)。NRF2的皮肤裂解或局部应用 激活剂足以诱导对口服食物抗原的致敏，这表明了一种新的机制。 致敏的，不同于目前的皮下范式，在这种范式中，食物过敏原被认为是物理上的 接触受损的皮肤屏障以编程产生过敏免疫反应。这项提议将检验这一假设 破坏皮肤屏障和/或激活角质形成细胞中Nrf2的局部化学佐剂促进 肠上皮和肠道树突状细胞上的信号 在皮肤-肠道-免疫轴中启动对符合的不可耐受口服过敏原的过敏增敏作用 收集全身和有条件的敲除小鼠。 这项提议为艾森斯坦博士成为免疫生物学、机制方面的专家提供了培训工具 过敏致敏和皮肤屏障功能，因此她可以将这一专业知识应用于 皮肤科，并协调她的临床和研究计划，以最大限度地影响翻译她的基本知识 特应性疾病临床治疗的科学研究。这个项目有可能解释 食物过敏发病率的现代上升以及湿疹与食物之间的临床联系 过敏，这可能会对公共健康产生重大影响，并导致新的治疗方法 食物过敏。此外，这些结果可能会对我们的基本理解产生重要的新见解 过敏性致敏的机制。

Project Summary/Abstract This proposal describes a rigorous training program leading to the career development of Dr. Anna Eisenstein as an independent scientist. The principal investigator is a physician scientist who recently completed Dermatology residency. Her career goal is to become an independent investigator studying the interplay between the skin barrier and immune function, with a particular interest in allergic disease. She proposes to expand her training in immunology and allergy through an intensive research experience under the co-mentorship of Dr. Andrew Wang and Dr. Joseph Craft as well as a preeminent advisory committee with leading scientists and physician scientists in immunology and dermatology. In addition to excellent mentoring, the proposal includes rigorous coursework, seminars and external meetings. These planned activities will equip her with the necessary skills to become a successful independent investigator. The research objective of this proposal is to understand why individuals with atopic dermatitis (eczema) are more prone to food allergies, both conditions whose prevalence are exponentially rising. Preliminary data reveals that environmental xenobiotics, like common over-the-counter medications and food preservatives, act as allergic adjuvants both when given orally or applied topically. These products were all found to activate the xenobiotic receptor, Nuclear factor erythroid 2-related factor (Nrf2). Cutaneous disruption or topical application of Nrf2 activators was sufficient to induce sensitization to orally introduced food antigens, suggesting a novel mechanism of sensitization, distinct from the current epicutaneous paradigm wherein food allergens are thought to physically contact a damaged skin barrier to program the allergic immune response. The proposal will test the hypothesis that disruption of the skin barrier and/or topical chemical adjuvants that activate Nrf2 in keratinocytes promote epidermal production of alarmins, which signal on the intestinal epithelium and gut resident dendritic cells to initiate allergic sensitization to coincident non-tolerized oral allergens in a skin-gut-immune axis using a unique collection of full body and conditional knock out mice. This proposal serves as a training vehicle for Dr. Eisenstein to become an expert in immunobiology, mechanisms of allergic sensitization, and cutaneous barrier function so that she can apply this expertise to the field of dermatology and harmonize her clinical and research programs for maximal impact in translating her basic science investigations to the clinical management of atopic diseases. This project has the potential to explain the modern rise in incidence of food allergies as well as the clinical association between eczema and food allergies, which could lead to significant influence on public health and lead to novel therapeutic approaches to food allergy. Furthermore, these results may yield important novel insights into our fundamental understanding of the mechanisms of allergic sensitization.