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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002765-05
Application #
2210519
Study Section
Research Training Review Committee (RTR)
Project Start
1992-07-01
Project End
1996-07-31
Budget Start
1996-07-01
Budget End
1996-07-31
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wang, A; Yokosaki, Y; Ferrando, R et al. (1996) Differential regulation of airway epithelial integrins by growth factors. Am J Respir Cell Mol Biol 15:664-72
Wang, A; Patrone, L; McDonald, J A et al. (1995) Expression of the integrin subunit alpha 9 in the murine embryo. Dev Dyn 204:421-31