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 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, responsible for scheduling our on-going meetings, seminars, and interactions with the Advisory groups (Internal and External), and a Tissue Culture and Immunoassay, an established core responsible for standardized, high quality viral and epithelial culture preparations that support research. We will 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 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.
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