Signaling in Airway Inflammation

哮喘是一个主要的公共卫生问题，现在被认为是一种气道炎症性疾病。气道粘膜的上皮表面代表与病毒病原体或吸入的过敏原接触的第一个细胞屏障。在与这些环境因子接触时，上皮细胞起着中心作用 通过激活细胞内信号传导途径分泌趋化因子和通过线粒体损伤分泌活性氧（ROS）来引发气道炎症。这些信号反过来又导致白细胞浸润到粘膜下层和相关的气道高反应性。该PPG应用程序由5个相互关联的项目（P1-P5）组成，研究ROS启动的信号传导是气道炎症过程早期的重要事件这一假设。我们提出了细胞因子、病毒和过敏原诱导特异性细胞内信号传导途径的具体假设，这些信号传导途径诱导遗传性过敏。 在炎症反应中起重要作用的程序。病毒复制过程中或植物过敏原相关蛋白产生的ROS诱导上皮细胞信号传导途径，控制趋化因子表达，改变线粒体功能，并诱导炎症。这些研究将导致识别新的目标 影响上皮细胞对常见哮喘加重剂的反应。本PPG中的项目将由一个管理核心（核心A）和一个组织培养和免疫测定核心（TCIC，核心B）提供支持，管理核心（核心A）负责安排我们正在进行的会议、研讨会以及与咨询小组（内部和外部）的互动，组织培养和免疫测定核心（TCIC，核心B）是一个既定的核心，负责标准化、高质量的病毒和上皮培养制备，支持所有5个研究项目。这些项目建立在由UTMB项目负责人（PL）建立的合作，多学科环境的基础上，通过联合出版物，招募新的研究人员到哮喘研究领域，以及开发新的研究支持来衡量。例如，PL已经成功地为NIH支持的蛋白质组学中心争取资金，以开发研究气道炎症的新技术，并在UTMB NIEHS环境健康中心的哮喘研究核心中担任领导职务。因此，在这个丰富和协同的环境中，该计划是唯一准备作出重大贡献，以了解病毒和过敏原诱导的细胞内信号传导途径对上皮细胞中的基因表达和氧化剂的机制和后果。

Asthma is a major public health problem now recognized to be an inflammatory disease of the airways. The epithelial surface of the airway mucosa represents the first cellular barrier to come into contact with viral pathogens or inhaled allergens. Upon contact with these environmental agents, the epithelium plays a central role in initiating airway inflammation by secreting chemokines through activation of intracellular signaling pathways and reactive oxygen species (ROS) through mitochondrial damage. These signals, in turn, are responsible for leukocytic infiltration into the submucosa and associated airway hyper-reactivity. This PPG application is composed of 5 inter-related projects (P1-P5) investigating the hypothesis that ROS initiated signaling is an important event early in the process of airway inflammation. We propose the specific hypothesis that cytokines, viruses and allergens induce specific intracellular signaling pathways that induce genetic programs important in the inflammatory response. ROS generated during viral replication or from plant allergen-associated proteins induce epithelial signaling pathways that control chemokine expression, alter mitochondrial function, and induce inflammation. These studies will result in identification of novel targets that influence epithelial cell responses to common exacerbants of asthma. The projects in this PPG will be supported by an Administrative Core (Core A), responsible for scheduling our on-going meetings, seminars, and interactions with the Advisory groups (Internal and External), and a Tissue Culture and Immunoassay Core (TCIC, Core B), an established core responsible for standardized, high quality viral and epithelial culture preparations that support all 5 research projects. These projects build on an established collaborative, multidisciplinary environment established by the Project Leaders (PLs) at UTMB, measured by joint publications, recruitment of new investigators to the field of asthma research, and development of new research support. For example, PLs have successfully competed for funds for a NIH-supported Proteomics Center to develop new technology to study airway inflammation, and serve in leadership capacities in the Asthma Research Core of the UTMB NIEHS Center for Environmental Health. Thus, in this rich and synergistic environment, this Program is uniquely poised to make significant contributions to understanding the mechanisms and consequences of viral and allergen induced intracellular signaling pathways on gene expression and oxidant tone in the epithelium.