The long-term goal of our research is to investigate the molecular mechanisms underlying pulmonary disorders, thereby identifying potential therapeutic targets for prevention and treatment of lung diseases. In this proposal, we will study how the Miz1-C/EBPd pathway regulates inflammation and acute lung injury (ALI). Using multifaceted approaches, we have recently uncovered that the transcription factor Miz1 inhibited TNFa or LPS-induced inflammatory response and expression of C/EBPd, which contributes to persistent inflammation, in a transcription-dependent manner in lung epithelial cells. Interestingly, Miz1 is phosphorylated upon TNFa stimulation. More importantly, the loss of Miz1 transcriptional repression activity augmented inflammation and ALI induced by LPS (bacterial lipopolysaccharide, a principal surface component of Gram-negative bacteria) in mice. We hypothesize that upon TNFa (or LPS) stimulation, Miz1 is phosphorylated leading to repression of C/EBPd expression, thereby preventing inflammation and ALI. This proposal is novel, as it will study how Miz1 inhibits TNFa or LPS-induced expression of inflammatory cytokines, and how the Miz1-C/EBPd pathway is regulated by inflammatory stimuli such as TNFa or LPS, and the pathophysiological role of the Miz1-C/EBPd pathway in inflammation and ALI in mice. This study will put forward a novel paradigm regarding the molecular mechanism that controls persistent inflammation and acute lung injury, which has significant clinical implications in pneumonia and chronic pulmonary obstructive diseases (CPOD). The completion of this study should provide a better understanding of the molecular mechanism underlying respiratory diseases.

Public Health Relevance

Inflammation and acute lung injury (ALI) have significant clinical implications in pneumonia and chronic pulmonary obstructive diseases (CPOD). Understanding how inflammation and ALI are regulated by the Miz1-C/EBP pathway will shed light on our understanding of the molecular mechanisms underlying pulmonary disorders and provide novel strategies for identifying potential therapeutic targets for prevention and treatmentof respiratory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114763-01A1
Application #
8630795
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (03))
Program Officer
Harabin, Andrea L
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$356,288
Indirect Cost
$125,681
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611