Regulation of Inflammation and Acute Lung Injury by the Transcription Factor Miz1

描述（由申请人提供）：我们研究的长期目标是研究肺部疾病的分子机制，从而确定预防和治疗肺部疾病的潜在治疗靶点。在本提案中，我们将研究Miz1-C/EBP¿通路如何调节炎症和急性肺损伤（ALI）。利用多方面的方法，我们最近发现转录因子Miz1以转录依赖的方式抑制TNF或lps诱导的炎症反应和C/EBP¿的表达，这有助于肺上皮细胞的持续炎症。有趣的是，Miz1在TNF刺激下被磷酸化。更重要的是，Miz1转录抑制活性的丧失增加了小鼠体内由LPS（细菌脂多糖，革兰氏阴性菌的主要表面成分）诱导的炎症和ALI。我们假设在TNF或LPS刺激下，Miz1被磷酸化，导致C/EBP表达抑制，从而预防炎症和ALI。这一提议是新颖的，因为它将研究Miz1如何抑制TNF -或LPS诱导的炎症细胞因子的表达，以及Miz1- c /EBP通路如何受到TNF -或LPS等炎症刺激的调节，以及Miz1- c /EBP通路在小鼠炎症和ALI中的病理生理作用。本研究将为研究持续炎症和急性肺损伤的分子机制提供一个新的范式，对肺炎和慢性肺阻塞性疾病（CPOD）的治疗具有重要的临床意义。本研究的完成将有助于更好地了解呼吸系统疾病的分子机制。

DESCRIPTION (provided by applicant): 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.