Grainyhead-Like Transcription factor in Airway Epithelium
Initial Award Abstract
Smoking disrupts the barrier of the respiratory tract lining, allowing toxins to penetrate into the tissue. This leads to injury and a tissue repair response, which ultimately leads to inflammatory diseases and possibly cancer. In order to understand tobacco-related respiratory diseases, it is important to investigate how respiratory epithelial development and homeostasis is controlled. In part, tobacco is likely to act by subverting the molecular pathways that normally control the homeostasis of the respiratory epithelium.
Our laboratory identified a gene encoding a transcription factor (protein that regulates other genes) which plays key roles in regulating the barrier of epithelia from divergent species. The founding member of this gene family is a fly protein Grainyhead, but our own work shows that the analogous gene in mammals, Grainyhead-like Epithelial Transactivator (Get-1/Grhl3), plays an important role in the formation of the skin barrier in mice. In addition to skin, the Get-1 gene is highly expressed in the developing epithelium of the trachea, bronchi and bronchioles, suggesting that it may also have important roles in this tissue.
To investigate the potential role of Get-1 in the respiratory epithelium, I have examined the tissue structure in the trachea of mice in which we inactivated the Get-1 gene. I found that structure of the tracheal epithelia is altered similar to that of mice where another transcription factor, p63, also very important for epithelial development, was inactivated. Consistent with this observation I found that expression of the p63 gene is reduced in the mice where the Get-1 gene is inactivated, suggesting that the Get-1 transcription factor regulates expression of the p63 gene. Based on these findings and the conserved functions of Grainyhead proteins in the differentiation of epithelial structures in many species, I hypothesize that Get-1 regulates p63 expression and plays an important role in the development and homeostasis of the respiratory epithelium.
To investigate the role of Get-1, I will first characterize in more detail the cellular changes in the tracheobronchial epithelium of mice deleted for the Get-1 gene. Then I will perform experiments to determine if Get-1 directly binds to and regulates p63 gene. Lastly, I will determine whether p63 expression is sufficient to prevent the abnormalities in the Get-1 deleted mice.
My hope is that these studies will provide fundamental insights into how development and homeostasis of the respiratory epithelium is regulated. Based on these findings, our understanding of tobacco-related lung diseases will be enhanced. Specifically, disruption of the normal tracheobronchial epithelium is likely to predispose to tobacco-related tracheal and lung cancers. These changes may also impact other tobacco-related disease with a strong inflammatory component such as chronic obstructive pulmonary disease. The training program will make me proficient in the biology of epithelial tissues and expose me to the importance of tobacco-related health problems. |