The alveolar epithelium is comprised of two morphologically distinct differentiated epithelial cells, type I and type II cells, both of which are thought to be critical for normal lung function. Although the establishment and maintenance of a normal alveolar epithelium is essential for mammalian life, factors controlling the expression of cellular phenotype are not well understood. In general, the regulation of phenotypic expression involves both activation and expression of gene transcription. Lack of suitable cell culture models or unique cell-specific biochemical markers has made it difficult to study regulation of phenotypic expression in the lung. In recent years, considerable progress has been made in the development of appropriate markers and in vitro systems. The experiments describes in this project concern the regulation of phenotypic expression of the alveolar epithelium, focusing on the expression of type I and type II cell phenotype- specific markers, both in vitro and in vivo. Recent observations, documented in previous publications and in the Progress Reports to Projects 3 and 4, suggest that mechanical factors play an important role in regulating alveolar epithelial phenotypic expression. The broad objectives of this proposal are two-fold: 1) to define the regulatory elements that dictate organ and cell- specificity for RTI40, which, within the lung, is a specific marker for type I cells; and 2) to define the mechanisms by which mechanical factors modulate cell phenotypic expression in vitro.
SPECIFIC AIMS 1. To determine the regions of the RT140 gene that direct tissue and cell- specific expression. 2. To determine the cis-acting elements and trans-acting factors responsible for regulating expression of RTI40. 3. To elucidate the elements responsible for mechanosensitive regulation of transcription of SP-C and RT140. 4. To identify some of the signaling pathways most likely to be involved in mechanical transduction of events in type I and type II cells.
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