The respiratory epithelium serves both as a polarized barrier against inhaled pathogens and toxins and as a source of several mediators involved in the initial response to airway injury. Fibronectin, an extracellular matrix protein, is believed to play an integral role in airway epithelial repair. In vitro, airway epithelial cells increase synthesis and secretion of fibronectin after stimulation with transforming growth factor-beta (TGF- beta), a cytokine believed to play a crucial role in tissue repair by modulating cellular growth and differentiation. The candidate has spent the last two years investigating the polarized regulation of alternative splicing and secretion of fibronectin by TGF-beta in tracheal epithelial cells and the proposed experiments are a logical extension of this research. First, the candidate will examine the secretion and alternative splicing of fibronectin in various polarized cell types using techniques such as immunoprecipitation, immunoblotting, and northern analysis. Second, crosslinking experiments using iodinated TGF-beta will be performed in order to determine whether the polarized response to TGF-beta is mediated by differential surface expression of TGF-beta receptors. Next, the candidate proposes to develop a transfection system using a fibronectin minigene construct in order to confirm and further study the effects of TGF-beta on alternative splicing of fibronectin. Transfection of fibronectin expression constructs will then be used to confirm and explore the role of the EIIIA domain as a targeting signal.
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