Eosinophil-nerve Interactions in Mouse Models of Dermatitis

皮炎小鼠模型中嗜酸性粒细胞与神经的相互作用

基本信息

批准号：
8834817
负责人：
David B Jacoby
金额：
$ 58.77万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8834817
关键词：
Abbreviations Acute Affect Affinity Allergens Allergic Allergic Contact Dermatitis Allergic Disease Allergic inflammation Anhydrides Antibodies Asthma Atopic Dermatitis Behavior Biopsy Brain-Derived Neurotrophic Factor Cell Communication Cell Nucleus Child Chronic Clinical Clinical Trials Coculture Techniques Contact hypersensitivity Cutaneous Cytoplasmic Granules Data Dermatitis Development Dinitrofluorobenzene Diphtheria Toxin Disease Drug Targeting Eosinophil Granule Proteins Eosinophil Major Basic Protein Eosinophil cationic protein Event Fiber Gene Proteins Genes Genetically Engineered Mouse Goals Growth Human In Vitro Inflammation Inflammatory Inflammatory Response Kidney Diseases Knock-in Mouse Lead Leukocytes Link Literature Lung diseases Mediating Modeling Mus Muscarinic M2 Receptor NGFR Protein NTRK1 gene Nerve Nerve Growth Factor Receptors Nerve Growth Factors Neurons Neurotrophin 3 Ovalbumin Pain Pathogenesis Patients Perception Pilot Projects Prevalence Process Proteins Pruritus Quality of life Relative (related person)Resources Role Sensory Skin Source Spinal Ganglia Staining method Stains Stimulus Structure Substance P Receptor Symptoms System Tachykinin Testing Therapeutic Touch sensation Transgenic Organisms afferent nerve allodynia aprepitant base behavioral response cost cutaneous sensory nerve disease diagnosis eosinophil eosinophil peroxidase experience granulocyte in vivo inflammatory pain insight mouse model neurophysiology neurotransmitter release neurotrophic factor neurotrophin 4 next generation novel relating to nervous system response skin disorder

项目摘要

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.

描述（由申请人提供）：皮炎小鼠模型中的嗜酸性粒细胞 - 神经相互作用项目摘要：嗜酸性粒细胞介导的募集、积累和/或活动（例如脱粒）一直是皮肤过敏性疾病的标志特征。这些事件还与这些患者的主要症状相关，包括皮肤的组织病理学变化和瘙痒等行为反应，这些反应通常会导致皮肤屏障功能的破坏。此外，在现有的皮炎小鼠模型中注意到嗜酸性粒细胞和过敏性皮肤炎症之间的这种联系，表明这些粒细胞的潜在作用。不幸的是，尽管存在很强的相关性，但嗜酸性粒细胞介导的导致皮肤变化、促进瘙痒反应等炎症症状的事件的定义仍然遥不可及。该合作提案的目标是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补这一差距。事实上，我们使用皮肤炎症模型的初步研究已经大大受益于嗜酸性粒细胞特异性抗体的可用性和我们先天性缺乏嗜酸性粒细胞的转基因小鼠系。我们在此提案中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），该模型允许诱导性和选择性地损失嗜酸性粒细胞。这项合作将集中我们使用炎症性疾病小鼠模型研究嗜酸性粒细胞的集体经验，以确定导致过敏性皮炎相关瘙痒的致病事件。特别是，通过选择性使用我们的新型体内小鼠模型和离体嗜酸性粒细胞-神经共培养研究，我们将测试中心假设，即皮肤浸润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，并增加速激肽的表达。反过来，这些重塑事件会导致与皮炎相关的瘙痒反应。