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/EBP? pathway regulates inflammation and acute lung injury (ALI). Using multifaceted approaches, we have recently uncovered that the transcription factor Miz1 inhibited TNF? or LPS-induced inflammatory response and expression of C/EBP?, which contributes to persistent inflammation, in a transcription-dependent manner in lung epithelial cells. Interestingly, Miz1 is phosphorylated upon TNF? 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 TNF? (or LPS) stimulation, Miz1 is phosphorylated leading to repression of C/EBP? expression, thereby preventing inflammation and ALI. This proposal is novel, as it will study how Miz1 inhibits TNF? or LPS-induced expression of inflammatory cytokines, and how the Miz1-C/EBP? pathway is regulated by inflammatory stimuli such as TNF? or LPS, and the pathophysiological role of the Miz1-C/EBP? 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 treatment of respiratory diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-G (03))
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Aggarwal, Neil Raj
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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