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.
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.
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