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Alterations in gene expression after tobacco smoke exposure

Institution: University of California, Davis
Investigator(s): Ken Yoneda, M.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6KT-0016 Award: $216,612
Subject Area: Pulmonary Disease
Award Type: New Investigator Awards

Initial Award Abstract
This research project targets the effects of both first and secondhand tobacco smoke in airways of young, otherwise healthy adults (18-24 years old). As a human subjects study, it avoids many of the artifacts inherent in animal and cell culture models designed to study human processes. By its nature, the information obtained will improve our understanding of the effects of tobacco smoke on humans.

Currently there remains an insufficient understanding of the early or subtle changes in the airways of young, asymptomatic, tobacco smoke-exposed adults. The discovery of genes that are up- or down-regulated due to tobacco smoke exposure, and changes in gene expression occurring after withdrawal of tobacco smoke, would profoundly increase our understanding of the pulmonary effects of first and secondhand smoke. This discovery would give focus to any further study of molecular changes in airways of tobacco smoke-exposed individuals. Without a better understanding of these mechanisms, further prevention and treatment interventions will be hindered. New molecular markers of protective gene regulation or tobacco smoke-induced injury, disease or cancer may be discovered. This discovery might well enable us to diagnose, treat or even prevent otherwise irreversible and untreatable tobacco-related diseases.

Final Report
The objective of this project was to identify early changes in the bronchial tubes of smokers who have no clinical evidence of tobacco smoke related disease. Some of the earliest and most important changes that occur in response to tobacco smoke are at the gene level. Early changes in gene expression are thought to be instrumental in the development of lung cancer and chronic bronchitis. To find tobacco smoke sensitive genes, we exposed primary human airway cell cultures to tobacco smoke and looked for genes that were markedly increased after tobacco smoke exposure. We screened 9,600 gene clones using a technique known as the micro array or gene chip technology. It makes possible, the simultaneous and rapid screening of thousands of genes for differential expression. Using this system, we identified genes that were over-expressed in response to tobacco smoke. We also looked at genes that were over-expressed in lung cancer cells compared to non cancerous lung tissue. By this approach, we were able to identify genes that we believe are induced by tobacco smoke and in lung cancer. We believe that these genes may play an important role in the induction of lung by tobacco smoke. Future studies will be aimed at further defining the mechanisms of gene over-expression, studying the genes that were repressed and in performing further large-scale gene screenings of tobacco smoke exposed cells and lung cancer. Understanding changes in gene expression is crucial to the understanding of the mechanisms of tobacco smoke induced diseases and in finding effective treatments for them. We believe our present and future studies will provide some of this essential information.

Differential gene expression in tobacco smoke exposed airway epithelial cell cultures using a cDNA micro-array system
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yoneda KY, Chmiel K, Wu R ABS
Yr: 2000 Vol: 161 Nbr: A145 Abs: Pg:

Selective activation of the AP-1, but not the NF-kB, transcription factor by tobacco smoke in the regulatiohn of gene expression in human airway epithelium
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Harper R, Zu C-H, Yoneda K, et al ABS
Yr: 2000 Vol: 161 Nbr: A536 Abs: Pg:

Activation of nuclear factor-kB transcriptional activity in airway epithelial cells by thioredoxin but not by N-acetyl-cysteine and glutathione.
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Harper R, Wu K, Chang MMJ, Yoneda K, Pan R, Reddy SPM, and Wu R ART
Yr: 2001 Vol: 25 Nbr: Abs: Pg: 178-185

Profiling smoke- and hydrogen peroxide-incuced gene expression patterns in human bronchial epithelial cells by high density DNA microarray membrane.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yoneda KY, Peck K, Chang MMJ, Chmiel K, Sher YP, Chen J, Yang PC, Chen T, and Wu R ART
Yr: 0 Vol: Nbr: Abs: Pg:

Mechanisms of signal transduction in tobacco smoke induced gene expression in airway epithelium.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yoneda KY ABS
Yr: 2001 Vol: 163 Nbr: Abs: Pg: A219