Eosinophil-nerve Interactions in Mouse Models of Dermatitis

描述(由申请人提供)：小鼠皮炎模型中嗜酸性粒细胞-神经的相互作用项目摘要：嗜酸性粒细胞的招募、聚集和/或活动(例如脱颗粒)一直是皮肤变态反应性疾病的特征。这些事件还与与这些患者相关的主要症状相关，包括皮肤的组织病理学变化和行为反应，如瘙痒，这些共同导致皮肤屏障功能的崩溃。此外，嗜酸性粒细胞和过敏性皮肤炎症之间的这种联系在现有的皮炎小鼠模型中也被注意到，这表明了这些粒细胞的潜在作用。不幸的是，尽管有很强的相关性，但嗜酸性粒细胞介导的事件会导致皮肤发生变化，从而促进发炎症状，如瘙痒反应，这一定义仍然遥不可及。这项合作提案的目标是通过利用我们使用肺部疾病的过敏原激发模型检查嗜酸性粒细胞活动的丰富经验来弥合这一差距。事实上，我们使用皮肤炎症模型进行的初步研究已经极大地受益于嗜酸性粒细胞特异性抗体的可获得性和我们的转基因小鼠品系，这些转基因小鼠都缺乏嗜酸性粒细胞。我们在这项建议中的目标是利用这些资源以及开发一种“下一代”基因敲入小鼠模型(IPHIL)，该模型允许诱导和选择性地丢失嗜酸性粒细胞。这项合作工作将集中我们使用炎症性疾病的小鼠模型研究嗜酸性粒细胞的集体经验，以确定与过敏性皮炎相关的瘙痒的致病事件。特别是，通过选择性地使用我们新颖的体内小鼠模型和体外嗜酸性粒细胞-神经共培养研究，我们将检验这一中心假设，即皮肤渗透的嗜酸性粒细胞和皮肤感觉神经之间的相互作用会增加神经的生长和分支，以及速激肽的表达增加。反过来，这些重塑事件促成了与皮炎相关的瘙痒反应。

DESCRIPTION (provided by applicant): Eosinophil - Nerve Interactions in Mouse Models of Dermatitis PROJECT SUMMARY: The recruitment, accumulation, and/or activities mediated by eosinophils (e.g., degranulation) have been hallmark features of cutaneous allergic diseases. These events also correlate with the dominant symptoms associated with these patients, including histopathological changes in the skin and behavioral responses such as itching that together often lead to a breakdown in cutaneous barrier functions. In addition, this link between eosinophils and allergic skin inflammation is noted in the available mouse models of dermatitis, suggesting an underlying role for these granulocytes. Unfortunately, despite the strong correlative relationship, the definition of eosinophil-mediated events leading to changes in the skin that promote inflammatory symptoms such as itch responses have remained out of reach. The goal of this collaborative proposal is to bridge this gap by exploiting our extensive experience examining eosinophil activities using allergen provocation models of lung disease. Indeed, our preliminary studies using skin inflammatory models have already greatly benefited from the availability of eosinophil-specific antibodies and our transgenic line of mice congenitall deficient of eosinophils. Our objective in this proposal is to exploit these resources as well as the development of a "next generation" gene knock-in mouse model (iPHIL) that permits the inducible and selective loss of eosinophils. This collaborative effort will focus our collective experiences studying eosinophils using mouse models of inflammatory diseases to define causative events contributing to the itching associated with allergic dermatitis. In particular, through the selective use of our novel in vivo mouse models and ex vivo eosinophil - nerve co-culture studies we will test the central hypothesis that interactions between skin infiltrating eosinophils and cutaneous sensory nerves increases nerve growth and branching, as well as increased expression of tachykinins. In turn, these remodeling events contribute to the itch response associated with dermatitis.