Eosinophil-nerve Interactions in Mouse Models of Dermatitis

项目概述：嗜酸性粒细胞的募集、积累和/或活动（如脱粒）是皮肤过敏性疾病的标志性特征。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改变和行为反应，如瘙痒，这两者通常导致皮肤屏障功能的破坏。此外，在现有的皮炎小鼠模型中发现了嗜酸性粒细胞和过敏性皮肤炎症之间的联系，这表明这些粒细胞可能起着潜在的作用。不幸的是，尽管有很强的相关关系，嗜酸性粒细胞介导的事件导致皮肤变化，促进瘙痒反应等炎症症状的定义仍然是不可触及的。这项合作提案的目标是利用我们使用过敏原激发肺部疾病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用性和我们的嗜酸性粒细胞先天缺陷小鼠转基因系。我们的目标是利用这些资源以及开发“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。这项合作努力将集中我们的集体经验，利用小鼠炎症疾病模型研究嗜酸性粒细胞，以确定导致过敏性皮炎相关瘙痒的致病事件。特别是，通过我们新颖的体内小鼠模型和体外嗜酸性粒细胞-神经共培养研究的选择性使用，我们将测试皮肤浸润性嗜酸性粒细胞和皮肤感觉神经之间的相互作用增加神经生长和分支，以及增加速激肽的表达的中心假设。反过来，这些重塑事件有助于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.