Very little is known about the molecular functions of the alveolar type 1 cell or about the regulatory mechanisms that lead to its distinctive architecture even though its formation is critical to successful lung development and to postnatal lung repair. This project if focused on the molecular regulation of T1 alpha, a rodent gene we cloned and characterized that is specific in lung for the type 1 cell, and explores the functions of the T1 alpha protein. During development T1 alpha is expressed mainly in epithelia of brain and lung; expression is down-regulated in organs other than lung as development proceeds. These studies will test the following hypotheses: 1. Expression of T1 alpha is transcriptionally regulated by classic interactions of protein transcription factors with cis-elements in the gene such that type l but not type ll cells express the protein. In non-expressing lung epithelial cells, such as airway cells, and brain cells T1 alpha may be regulated by methylation of the promoter. 2. In vitro and likely in vivo type l and ll cells can express the molecular phenotype of either cell but do not express both simultaneously. 3. T1 alpha protein acts as a modulator of cellular functions related to movements of ions and water across or through type 1 cells. Based on known functions of the choroid plexus and ciliary epithelium of the eye that also express T1 alpha. Using molecular, cellular, and transgenic approaches we will test these hypotheses in lung and brain cell lines, in primary lung cells, lung and brain tissues, and in intact animals.
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