A balancing act between transcriptional "activators" and "repressors" appears to play a key role in maintaining tissue homeostasis. However, shifting the balance in favor of activator or repressor functions can deregulate transcription (the initial step in gene expression), ultimately leading to a pathologic state. Indeed, emerging data have causally linked abnormal expression of genes involved in injury and repair to a wide variety of environmental insults, which either cause or enhance susceptibility to a variety of pathologic states, including acute and chronic lung diseases. This competing renewal application is focused on expanding our ongoing studies of the novel roles of Fra1 transcription in lung injury and repair. Fra1 is a dimeric partner of AP1 (Jun/Fos), which is activated by environmental insults and regulates gene expression that is involved in both normal and pathologic processes. During the last funding period, we have shown that interplay between the upstream promoter elements and the serum response element drives the Fra1 induction. We have shown that ectopic Fra1 promotes lung cell motility and invasion in vitro, but it requires other activated protooncogene(s) to impart its oncogenic potential in vivo. Although emerging data have unequivocally demonstrated a causative role for Fra1 in cancer cell progression and invasion, the exact role of Fra1 in non-malignant lung diseases remains unclear. Intriguingly, we have found that deletion of Fra1 confers increased protection against prooxidant-induced lung injury, when compared to results in control mice. We have also found that Fra1-deficient cells are remarkably more resistant than Fra1-sufficient cells to prooxidant-induced cell death. In reporter assays, ectopic Fra1 expression decreased both AP1-dependent and -independent transcriptional responses in lung epithelial cells. Based on these novel preliminary observations, we hypothesize that Fra1 functions as a "transcriptional repressor," thereby playing a key role in promoting cellular injury and lung pathogenesis. To test our hypothesis and to further to dissect Fra1 promoter regulation, we propose the following specific aims: 1) To determine the mechanisms involved in protection against prooxidant exposure by Fra1 deficiency using gene-targeted mice and experimental models of acute lung injury, 2) to dissect the critical factors that regulate basal-level and inducible Fra1 expression in vitro;and 3) to examine the patterns of Fra1 induction in lung disease and during injury and repair by using tdTomato-based noninvasive optical imaging in vivo and ex vivo. The proposed studies are not only novel in terms of elucidating the biology and functions of Fra1 but will also provide critical insights into the mechanistic basis underlying prooxidant-induced cellular stress and non-malignant lung pathogenesis. Because cellular stress is an integral part of many lung diseases and malignancy, these results could enable us to target Fra1, or steps that specifically regulate Fra1, as novel therapeutic agent(s).

Public Health Relevance

Understanding the role of Fra1 in acute lung injury and delineating the mechanisms underlying FRA1 induction and the development of noninvasive red florescence-based optical imaging of human FRA1 promoter activation in vivo will be helpful in allowing us to monitor and track the host transcriptional response to proxidants and toxicants over time in cells that are undergoing injury and repair or are associated with a pathological/disease state. The results obtained from this study will be of great significance for our understanding of disease mechanisms such as oxidative stress, DNA damage, and inflammation regulated by MAP kinase/AP1-Fra1 signaling in response to stressful stimuli.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011863-10
Application #
8206667
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
2002-09-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
10
Fiscal Year
2012
Total Cost
$346,221
Indirect Cost
$125,698
Name
University of Illinois at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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