and specific aims): The integrity of the alveolar epithelium is critical for normal lung function. This barrier is continuously exposed to potentially injurious environmental, local, and systemic stimuli. How this epithelium is maintained and repaired, what cell populations are involved, and how these homeostatic and reparative processes are regulated remain obscure. Histopathological evidence has suggested that, of the two alveolar epithelial cell types, type II (AT2) cells may be capable of both self-renewal and transdifferentiation into type I (AT1) cells. However, the numerous cell types that compromise the adult lung, the complex pulmonary cytoarchitecture, and the lack (until recently) of reliable, non-morphological markers for defining alveolar epithelial cell (AEC) phenotype have precluded verification of this presumption. The long-range goal of our research is to understand how cellular differentiation and its regulation contribute to maintenance and repair of the alveolar epithelium in the mature lung. To begin to address this problem, the projects proposed herein will test the following hypotheses: 1) transdifferentiation of AT2 and AT1 cells is definable by cell type-specific gene expression; 2) AT2 and AT1 cell type-specific genes are coordinately up- and/or down-regulated during modulation of AEC phenotype; and 3) AEC transdifferentiation involves transcriptional regulation of cell type-specific genes.
The specific aims are: 1) to analyze regulation of phenotype-specific gene expression during AEC differentiation; 2) to identify new type I (and type II) AEC-specific genes; and 3) to investigate regulation of AEC differentiation by the expression and interaction of trans-acting factors with cell type-specific genes.
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