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

转录因子 Miz1 对炎症和急性肺损伤的调节

• 批准号: 8787773
• 负责人: JING LIU
• 金额: $ 38.51万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787773
• 关键词: Acute Lung Injury; Affect; BTB/POZ Domain; Bacteria; Binding; CCAAT-Enhancer-Binding Proteins; Candidate Disease Gene; Cells; Chronic Obstructive Airway Disease; Clinical; Cytoplasm; Data; Epithelial Cells; Genetic Transcription; Goals; Gram-Negative Bacteria; HDAC1 gene; Health; Hematopoietic; Human; Immune response; Inflammation; Inflammatory; Inflammatory Response; Injury; Invaded; Kinetics; Light; Lipopolysaccharides; Lung; Lung diseases; MAPK8 gene; Molecular; Mus; Myeloid Cells; NF-kappa B; Natural Immunity; Nuclear; Organ failure; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Play; Pneumonia; Prevention; Protein Kinase; Pseudomonas aeruginosa; Recruitment Activity; Regulation; Reporting; Repression; Research; Resolution; Role; Site; Stimulus; Surface; TNF gene; Testing; Tissues; Transcriptional Activation; Tumor Necrosis Factor-alpha; Up-Regulation; Virus; activating transcription factor 3; adaptive immunity; base; chromatin remodeling; cytokine; gene repression; in vivo; mortality; mutant; novel; novel strategies; pathogen; prevent; promoter; stoichiometry; therapeutic target; transcription factor

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.

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)。通过多方面的方法，我们最近发现转录因子 Miz1 在肺上皮细胞中以转录依赖性方式抑制 TNF 或 LPS 诱导的炎症反应和 C/EBP 的表达，从而导致持续性炎症。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加剧了LPS（细菌脂多糖，革兰氏阴性细菌的主要表面成分）在小鼠体内引起的炎症和ALI。我们推测，在 TNF（或 LPS）刺激下，Miz1 被磷酸化，导致 C/EBP 表达受到抑制，从而预防炎症和 ALI。该提案是新颖的，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M​​iz1-C/EBP?通路如何受到TNF?或LPS等炎症刺激物的调节，以及Miz1-C/EBP?通路在小鼠炎症和ALI中的病理生理学作用。这项研究将提出一个关于控制持续性炎症和急性肺损伤的分子机制的新范式，这对于肺炎和慢性肺阻塞性疾病（CPOD）具有重要的临床意义。这项研究的完成应该可以更好地了解呼吸系统疾病的分子机制。