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: 8630795
• 负责人: JING LIU
• 金额: $ 39.59万
• 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/8630795
• 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; 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; public health relevance; stoichiometry; stress-activated protein kinase 1; therapeutic target; transcription factor

Project Summary/Abstract 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.

项目摘要/摘要 我们研究的长期目标是研究肺源性肺炎的分子机制。 因此，为预防和治疗肺部疾病确定了潜在的治疗目标。 在这个方案中，我们将研究Miz1-C/EBPd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抑制了 TNFa或内毒素诱导的炎症反应和C/EBPd的表达 肺上皮细胞以转录依赖的方式持续发炎。有趣的是，Miz1 在TNFa刺激下被磷酸化。更重要的是，Miz1转录抑制的丧失 活性增强内毒素(主要是细菌脂多糖)诱导的炎症和ALI 革兰氏阴性菌的表面成分)。我们假设在肿瘤坏死因子(或脂多糖) 刺激后，Miz1被磷酸化，导致C/EBPd表达受抑，从而阻止 炎症和ALI。 这一建议是新颖的，因为它将研究Miz1如何抑制TNFa或内毒素诱导的 炎性细胞因子，以及Miz1-C/EBPd通路如何受炎症刺激等调节 以及Miz1-C/EBPd通路在炎症和ALI中的病理生理作用 在老鼠身上。 这项研究将提出一种新的关于控制分子机制的范式 持续性炎症和急性肺损伤在肺炎中具有重要的临床意义 和慢性肺阻塞性疾病(CPOD)。这项研究的完成应会提供一个 更好地理解呼吸系统疾病的分子机制。