A significant function of the pulmonary epithelium is to protect the lung from damage while maintaining a homeostatic balance between these protective processes and the processes allowing for the exchange of gasses. One of the pulmonary epithelial cell types involved in the maintenance of this homeostatic balance is the non-ciliated secretory cell of the bronchiolar epithelium, the Clara cell. The major secretory product of the Clara cell is a homodimeric 16 kDa protein, Clara cell secretory protein, CCSP. Biochemical analysis and gene ablation studies have demonstrated that this protein protects the lungs in cases of environmental insult, such as a hyperoxic challenge. Glucocorticoids, cytokines and oxygen regulate the expression of this gene. Initial analysis of the elements regulating the expression of this gene has defined transcription factors which govern the pulmonary specific expression of this gene. It is the goal of this proposal to investigate the means by which cytokines and oxygen affect the interactions of these transcription factors in the regulation of the expression of the CCSP gene. This will be accomplished by achieving the following specific aims: The identification of elements in the distal promoter of the CCSP gene regulating Clara cell specific expression. Identification of the elements in the CCSP promoter which are responsible for regulation by Interferon-gamma (IFN-gamma). Investigation of the molecular mechanism governing the repressive effect of hyperoxia on CCSP expression. Examine the physiological effects of hyperoxia on a mouse whose CCSP gene promoter elements have has been made irresponsive to oxygen. The definition of the interactions of these regulatory elements will allow the identification of the molecular mechanisms governing the physiological regulation of this gene. An understanding of these processes will allow the development of approaches to protect the lung against hyperoxic and inflammatory insult. Therefore, the goal of this proposal is to define the molecular mechanisms involved in the physiological expression of the CCSP gene and examine the physiological consequences of disrupting these molecular processes.
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