Eosinophil trafficking in fungal allergic asthma

真菌过敏性哮喘中的嗜酸性粒细胞贩运

• 批准号: 8496369
• 负责人: GLENN Paul DORSAM
• 金额: $ 43.48万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496369
• 关键词: Accounting; Affect; Allergic; American; Antifungal Agents; Appointment; Architecture; Aspergillus fumigatus; Asthma; Autocrine Communication; Breathing; Cells; Charge; Chromatin; Chromatin Structure; Chronic; Clinic; Clinical; Collaborations; Diagnostic; Disease; Educational process of instructing; Emergency Situation; Eosinophilia; Epithelium; Extrinsic asthma; Fibrosis; Future; Goals; Health; Healthcare; Homing; Hospitalization; Human Resources; Hyperplasia; Immune Cell Activation; Immunology; Knockout Mice; Laboratories; Link; Lung; MMP9 gene; Measurement; Mediating; Medical center; Mission; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Mus; Neuropeptides; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Positioning Attribute; Production; Productivity; Proteins; Protocols documentation; Public Health; Publishing; Qualifying; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Role; Science; Scientist; Signal Pathway; Signal Transduction; Students; Syndrome; Techniques; Testing; Tissues; Training; Transcription Coactivator; Transcription Factor AP-1; United States National Institutes of Health; Vasoactive Intestinal Peptide; Visit; Work; airway inflammation; autocrine; base; career; chemokine; chromatin immunoprecipitation; chromatin remodeling; cost; cytokine; eosinophil; fungus; granulocyte; human morbidity; immunopathology; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; medical schools; migration; mouse model; novel; programs; promoter; public health relevance; respiratory smooth muscle; response; trafficking; undergraduate student; vasoactive intestinal peptide 2 receptor

DESCRIPTION (provided by applicant): Asthma is a chronic pulmonary condition affecting 34.1 million Americans with an annual cost of $19.7 billion. Sensitization to fungi in the context of asthma presents a severe clinical scenario that is difficult to treat, accounting for a disproportionately large number of emergency center visits and hospitalizations. The long term goal of our research is to understand the beneficial and detrimental effects of eosinophils in the context of the allergic lung and fungal exposure. The objective of this application is to link recruitment and trafficking of eosinophils in the lung lumen to signaling by a neuropeptide called vasoactive intestinal peptide (VIP). Our central hypothesis is that VIP, through an autocrine mechanism, signals through its VPAC2 receptor to regulate recruitment (chemokinesis) and MMP9 production (invasion) of eosinophils, facilitating their entry to the lumen of the lung. This hypothesis is based on our previously published work showing a significant reduction of eosinophils in the lung lumen of VPAC2 deficient mice after fungal challenge. Defining the molecular mechanisms that guide eosinophil trafficking will provide targets to regulate these cells to help facilitate their potential benefits and limit their pathologic effects and is the ratonale for this work. We will test our central hypothesis with two specific aims. We will determine the extent to which: 1) VIP/VPAC2 autocrine signaling controls eosinophil egression into the pulmonary lumen and 2) VPAC2 signaling is necessary for MMP9 de novo expression in eosinophils. These aims will utilize VPAC2 wild type (C57BL/6) and knockout mice in an inhalation model of Aspergillus fumigatus allergic asthma that was developed by our research team. Aim one will provide evidence that an autocrine loop of VIP/VPAC2 activates a chemokenetic program in eosinophils critical for lung recruitment. Aim two will establish a molecular mechanism for eosinophil invasion into lung lumen by restructuring the chromatin architecture to a permissive state at the MMP9 promoter inducing its expression and secretion. The innovation for this proposal is connecting neuropeptide signaling to explain eosinophilia in an in vivo fugal allergic asthma model to improve training of NDSU students in molecular (Dr. Dorsam) and whole-body modeling (Dr. Schuh) and through training collaborations hosted in the clinical laboratories of Dr. Hirohito Kita (eosinophil techniques, Mayo Clinic) and Dr. Sinisa Dovat (chromatin remodeling, Hershey Medical School).

描述（由申请人提供）：哮喘是一种慢性肺部疾病，影响3410万美国人，每年花费197亿美元。在哮喘的背景下，真菌致敏呈现出一种难以治疗的严重临床情况，占急诊中心就诊和住院的不成比例的大量。我们研究的长期目标是了解嗜酸性粒细胞在过敏性肺和真菌暴露的背景下的有益和有害影响。该应用的目的是将肺腔内嗜酸性粒细胞的募集和贩运与一种称为血管活性肠肽（VIP）的神经肽的信号传导联系起来。我们的中心假设是VIP通过自分泌机制，通过其VPAC2受体发出信号，调节嗜酸性粒细胞的募集（趋化作用）和MMP9的产生（入侵），促进它们进入肺腔。这一假设是基于我们之前发表的研究成果，该研究表明真菌侵袭后VPAC2缺陷小鼠肺腔内嗜酸性粒细胞显著减少。确定引导嗜酸性粒细胞运输的分子机制将为调节这些细胞提供靶标，以帮助促进它们的潜在益处并限制它们的病理作用，这是这项工作的基本原理。我们将用两个具体目标来检验我们的中心假设。我们将确定在多大程度上：1)VIP/VPAC2自分泌信号控制嗜酸性粒细胞向肺腔的迁移，2)VPAC2信号对于嗜酸性粒细胞中MMP9从头表达是必要的。这些目的将利用VPAC2野生型（C57BL/6）和敲除小鼠在烟曲霉过敏性哮喘的吸入模型中，由我们的研究小组开发。目的一将提供证据，证明VIP/VPAC2的自分泌环激活嗜酸性粒细胞的趋化动力学程序，对肺募集至关重要。目的二将通过重组MMP9启动子的染色质结构，使其处于允许状态，从而诱导其表达和分泌，从而建立嗜酸性粒细胞侵入肺腔的分子机制。该提案的创新之处是将神经肽信号传导与体内真菌过敏性哮喘模型中的嗜酸性粒细胞联系起来，以改善NDSU学生在分子（Dorsam博士）和全身建模（Schuh博士）方面的培训，并通过Hirohito Kita博士（嗜酸性粒细胞技术，梅奥诊所）和Sinisa Dovat博士（染色质重塑，好时医学院）的临床实验室主持的培训合作。