This application seeks to elucidate the mechanisms of transcriptional regulation of lung-specific genes during acute respiratory infection and inflammation. Homeostasis of lung function during infection is likely regulated by critical lung-specific genes. Important lung homeostatic proteins, including surfactant protein (SP) genes and the Clara cell secretory protein (CCSP), are markedly decreased following acute infection. Preliminary data herein indicate that CCSP gene expression is down-regulated through attenuation of promoter function, specifically in the proximal transactivating promoter region containing several critical transactivating binding sites. Likewise, new findings implicate the role of inflammatory mediators, in particular TNF-alpha, in the regulation of lung gene transcription during the host response to acute infection. Strong similarities exist in the proximal promoter elements of CCSP and SP genes, suggesting that mechanisms of transcriptional regulation of these genes may be coordinated both in normal and diseased lung. Using CCSP transcriptional regulation as a model, transcriptional regulation and DNA-protein interactions of lung-specific genes can now be studied in both in vitro and in vivo systems using a transgenic approach. Specifically, this application proposes to delineate the DNA-protein interactions in the CCSP promoter loci and elucidate mechanisms of transcription factor regulation that aberrantly regulate lung-specific gene expression by specific inflammatory mediators during the host response to acute infection. The use of CCSP promoter regulation as a model for understanding transcriptional regulation in the mouse lung has distinct advantages, including the ability to develop transgenic animals for the study of lung-specific transcriptional regulation and DNA-protein interactions in vivo. Using this approach, the mechanisms of transcriptional regulation of lung-specific genes by pathogens or inflammatory mediators can be assessed in vivo, a strategy that is often unavailable for other experimental studies. Elucidation of the DNA-protein interactions and transcription factor regulation that attenuate lung-specific transcription will likely be important to understand the mechanisms of diminished lung function during severe respiratory infections and inflammation.
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