Mechanisms of IgE-mediated regulation of monocyte antiviral response pathways

项目摘要/摘要： 病毒感染与包括过敏性哮喘在内的过敏性疾病的恶化高度相关， 特应性皮炎和过敏性鼻炎。免疫球蛋白介导的过敏性致敏作用已被证明会削弱抗病毒作用 先天性免疫细胞的反应，如单核细胞促进促炎细胞因子的分泌， 破坏吞噬，抑制病毒诱导的成熟，干扰素的产生，并改变CD4T细胞的启动。 这些发现表明，IgE介导的信号在调节先天抗病毒信号通路中发挥了作用， 然而，人们对这些观察背后的分子机制知之甚少。考虑到重要的 过敏性疾病的发病率和经济影响，彻底了解IgE介导的影响 抗病毒反应对于发现治疗病毒和过敏性疾病的新疗法至关重要。这样做的目的是 研究确定IgE介导的过敏刺激如何抑制单核细胞抗病毒反应 细胞功能。使用原代人类单核细胞，我们将利用已建立的分子和生化 与先进的流式细胞仪技术相结合的技术(流式细胞仪成像和质量 细胞学)和转录组分：(目标1)确定IgE介导的信号组件如何调节早期 抗病毒识别途径，(目标2)决定了IgE诱导的IL-10的调节机制 干扰素受体信号传递，和(AIM 3)通过比较单核细胞抗病毒药物来翻译体外研究结果 高、低血清免疫球蛋白E个体的反应。这些研究将填补我们目前知识中的一大空白 了解IgE介导的过程如何调节抗病毒反应，以促进病毒诱导的过敏性加重。 Regina K.Rowe博士，医学博士，现任儿科传染病助理教授 罗切斯特大学医学中心。年，她在圣路易斯的华盛顿大学获得博士学位 分子微生物学和微生物致病，她研究了汉坦病毒与 呼吸道上皮。然后她在圣路易斯大学接受了医学培训，随后是儿科 在德克萨斯大学西南分校接受住院医师和传染病研究员培训，她在那里从事博士后研究 重点研究了过敏刺激对单核细胞诱导的T细胞活化的影响。这个职业发展奖 将通过细胞信号机制、高级流程培训来扩展她在系统免疫学方面的专业知识 细胞学方法和生物信息学。作为一名儿科内科科学家，她将利用自己的技能 传染病专家接受过人类免疫学和病毒学方面的培训，以建立一个科学平台 在人类疾病的背景下回答一系列涉及宿主-病原体相互作用的问题。她 创新的方法有可能找到治疗病毒引起的过敏性疾病的新疗法， 并最终防止疾病的发展、恶化和发展。

Project Summary/Abstract: Virus infections are highly associated with the exacerbation of allergic diseases including allergic asthma, atopic dermatitis, and allergic rhinitis. IgE-mediated allergic sensitization has been shown to impair antiviral responses by innate immune cells such as monocytes- enhancing pro-inflammatory cytokine secretion, disrupting phagocytosis, and inhibiting virus-induced maturation, IFN production, and altering CD4 T cell priming. These findings suggest a role for IgE-mediated signals in modulating innate antiviral signaling pathways, however little is known regarding the molecular mechanisms behind these observations. Given the significant morbidity and economic impact of allergic diseases, a thorough understanding of IgE-mediated effects on antiviral responses is critical for the discovery of new therapeutics for viral and allergic diseases. The goal of this study is to determine how IgE-mediated allergic stimulation inhibits monocyte antiviral responses to regulate cellular functions. Using primary human monocytes, we will utilize established molecular and biochemical techniques in combination with advanced flow cytometry techniques (flow cytometry imaging and mass cytometry) and transcriptomics to: (Aim 1) determine how IgE-mediated signaling components regulate early antiviral recognition pathways, (Aim 2) determine the mechanisms by which IgE-induced IL-10 regulates interferon receptor signaling, and (Aim 3) translate the in vitro findings by comparing monocyte antiviral responses in individuals with high and low serum IgE. These studies will fill a large gap in our current knowledge of how IgE-mediated processes modulate antiviral responses to promote virus-induced allergic exacerbations. Dr. Regina K. Rowe, M.D. Ph.D. is currently an Assistant Professor of Pediatric Infectious Diseases at the University of Rochester Medical Center. She received her Ph.D. from Washington University in St. Louis in Molecular Microbiology and Microbial Pathogenesis where she investigated the interactions of hantaviruses with the respiratory epithelium. She then received medical training at St. Louis University followed by Pediatric Residency and Infectious Disease Fellowship training at UT Southwestern where her postdoctoral research focused on the effects of allergic stimulation on monocyte-induced T cell priming. This career development award will expand her expertise in systems immunology through training in cell signaling mechanisms, advanced flow cytometry methods, and bioinformatics. As a pediatric physician-scientist, she will utilize her skills as an infectious disease specialist trained in both human immunology and virology to establish a scientific platform to answer a breadth of questions involving host-pathogen interactions in the context of human disease. Her innovative approaches have the potential to identify new therapeutics to treat virus-induced allergic diseases, and ultimately prevent disease development, exacerbation, and progression.