Mechanisms of Engineered Nanomaterial Modulation of Skin Immune Responses

项目摘要 该项目建立在我们的新发现之上，即局部应用工程纳米材料（ENM）可以 调节皮肤中的过敏性免疫反应。使用接触性超敏反应（CHS）小鼠模型， 发现一些ENM抑制治疗相关的皮肤炎症， 加重过敏症状，提示皮肤ENM暴露的危害增加 特别是对于患有变应性接触性皮炎（ACD）的个体。事实上，15-20%的 美国人被诊断患有ACD，占报告的职业性皮肤病的95% 也是患者去看皮肤科医生的第三大常见原因。随着工业和 消费者使用ENM的风险越来越大，ACD患者可能同时出现 皮肤接触环境过敏原或化学致敏剂和ENM通过使用纳米- 产品或职业暴露。这个项目的主要目标是了解 ENM如何调节过敏性皮肤免疫应答的细胞和分子机制， 目前我们对此知之甚少。我们已经确定了一个早期的行动窗口， ENM发挥其作用，我们的数据表明与肥大细胞（MC）的重要联系。的 该项目的中心假设是ENM在皮肤中发挥免疫调节作用 通过改变早期MC激活的过敏反应。我们将研究ENM如何改变 MC激活机制及其与其他表皮细胞类型的串扰，使用创新的活 小鼠活体成像和常见技术的新方法。一组体外测定是 建议进一步研究环境影响指标是否对市政局有直接影响，或间接影响市政局， 由其他表皮细胞类型产生的旁分泌信号，从而抑制或加剧 CHS激发反应。该项目将产生评估以下风险/收益所需的知识： 非预期/预期ENM皮肤暴露并产生用于预防过敏性皮肤的新方法 炎症

Project Summary This project builds on our novel finding that topically applied engineered nanomaterials (ENMs) can modulate allergic immune responses in skin. Using a contact hypersensitivity (CHS) mouse model we discovered that some ENMs suppress skin inflammation which is therapeutically relevant and others exacerbate allergic symptoms suggesting an increased hazard for cutaneous ENM exposure particularly for individuals whom suffer with allergic contact dermatitis (ACD). In fact, 15-20% of the US population is diagnosed with ACD which accounts for 95% of reported occupational skin disease and is the third most common reason patients visit a dermatologist. With the expanding industrial and consumer use of ENMs there is a growing risk that individuals with ACD may simultaneously come into skin contact with environmental allergens or chemical sensitizers and ENMs through use of nano- enabled products or from occupational exposures. The primary goal of this project is to understand the cellular and molecular mechanisms of how ENMs modulate allergic skin immune responses for which little is currently understood. We have defined an early time window of action within which ENMs exert their effects and our data suggests an important connection with mast cells (MCs). The central hypothesis of this project is that ENMs exert immunomodulatory effects in skin allergic responses by altering early MC activation. We will examine how ENMs alter the mechanisms of MC activation and their cross talk with other epidermal cell types using innovative live mouse intravital imaging and common techniques in novel ways. A panel of in vitro assays are proposed to further examine if ENMs exert a direct effect on MCs or act indirectly by altering paracrine signals generated by other epidermal cell types thereby suppressing or exacerbating the CHS elicitation response. This project will generate knowledge needed to assess the risk/benefit of unintended/intended ENM skin exposure and generate novel approaches for preventing allergic skin inflammation.