Resistin-like molecules in pulmonary fibrosis

肺纤维化中的抵抗素样分子

• 批准号: 8666587
• 负责人: SEM H PHAN
• 金额: $ 48.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666587
• 关键词: Address; Alveolar; Animal Model; Apoptosis; Apoptotic; Biochemical; Bone Marrow; Cells; Chimera organism; Chronic; Collagen Gene; Complex; Development; Disease; Drug Formulations; Elements; Epithelial Cells; Family; Family member; Fatal Outcome; Fibroblasts; Fibrosis; Future; Gene Expression; Gene Targeting; Genes; Hamman-Rich syndrome; In Vitro; Indium; Inflammatory; Knockout Mice; Light; Lung; Lung diseases; Mediator of activation protein; Molecular; Mus; Myeloid Cells; Myofibroblast; Pathogenesis; Play; Process; Property; Protein Family; Protein Isoforms; Proteins; Pulmonary Fibrosis; Regulation; Research; Resistance; Rodent Model; Role; STAT6 gene; Sequence Homology; Signal Pathway; Stem cells; Stimulus; Testing; Transcriptional Regulation; Transgenic Organisms; cytokine; effective therapy; expression vector; improved; in vivo; injured; insight; lung injury; macrophage; member; neutralizing antibody; novel; novel therapeutic intervention; overexpression; progenitor; public health relevance; receptor; resistin; response; tool

DESCRIPTION (provided by applicant): Chronic progressive fibrotic lung diseases, such as idiopathic pulmonary fibrosis, remain essentially untreatable with urgent need for elucidating mechanisms to aid in discovery of novel effective therapy. These diseases involve complex and intricate interactions between both endogenous lung as well as bone marrow derived cells via a myriad of mediators, the full spectrum of which has not yet been identified. RELM¿ (resistin-like molecule ¿)/FIZZ1 (Found in Inflammatory Zone 1), a member of the resistin family of molecules is recently found to be highly induced in an animal model of lung fibrosis, and shown to activate fibroblasts with promotion of myofibroblast differentiation and enhancing their resistance to apoptotic stimuli. It is predominantly expressed by lung epithelial cells, which can be potently induced by Th2 cytokines via STAT6. Deficiency of these elements in mice diminishes lung RELM¿ expression that correlates with diminished lung fibrosis. Despite this suggestive evidence for a role in fibrosis, the precise in vivo roles of RELM¿ in fibrosis remain unclear. The central hypothesis of this project is that RELM¿ and its homologous second family member, RELM¿/FIZZ2, are induced in epithelial cells during lung injury resulting in activation of adjacent fibroblasts and promotion of myofibroblast differentiation, as well as participate in recruitment o bone marrow-derived cells. Interaction between these cellular elements initiated by these mediators leads to the promotion of fibrosis and its progression. The Aims are to, 1) analyze effects of RELM¿/¿ deficiency and overexpression on normal and injured lung, 2) evaluate the role of RELM¿/¿ in bone marrow-derived fibroblast-like progenitor cell recruitment and consequent impact on fibrosis, 3) identify their cellular receptors, primary downstream signaling pathways and regulated target genes, and 4) examine the regulation of RELM¿ gene expression in lung type II alveolar epithelial cells. The approaches will exploit a combination of biochemical and molecular tools to dissect the molecular mechanisms involved in regulating their expression, and will use the already available transgenic murine strains necessary to confirm their importance in vivo. Bone marrow chimera mice will be used to assess cell recruitment to the lung.

描述（由申请人提供）：慢性进行性纤维化肺病，例如特发性肺纤维化，基本上仍然无法治疗，迫切需要阐明机制以帮助发现新型有效疗法。这些疾病涉及内源性肺以及骨髓来源的细胞之间通过无数介质的复杂和错综复杂的相互作用，其全部谱尚未被鉴定。RELM（抵抗素样分子））/FIZZ 1（在炎症区1中发现），最近发现在肺纤维化的动物模型中高度诱导的分子的ECORN家族的成员，并且显示激活成纤维细胞，促进肌成纤维细胞分化并增强其对凋亡刺激的抗性。它主要由肺上皮细胞表达，其可以通过STAT 6由Th 2细胞因子有效诱导。这些元素在小鼠中的缺乏减少了与减少肺纤维化相关的肺RELM？表达。尽管有这一提示性证据表明RELM在纤维化中的作用，但RELM在纤维化中的确切体内作用仍不清楚。的 该项目的中心假设是，RELM <$及其同源第二家族成员RELM <$/FIZZ 2在肺损伤期间在上皮细胞中被诱导，导致邻近的 成纤维细胞和促进肌成纤维细胞分化，以及参与骨髓源性细胞的募集。由这些介质引发的这些细胞元件之间的相互作用导致促进纤维化及其进展。目的是：1）分析RELM ™/™缺陷和过表达对正常和受损肺的影响，2）评估RELM ™/™在骨髓源性成纤维细胞样祖细胞募集中的作用以及随之而来的对纤维化的影响，3）识别它们的细胞受体、主要下游信号通路和受调节的靶基因，以及4）检查RELM ™的调节肺II型肺泡上皮细胞中的基因表达。这些方法将利用生物化学和分子工具的组合来剖析参与调节其表达的分子机制，并将使用已经可用的转基因鼠株来确认其在体内的重要性。骨髓嵌合体小鼠将用于评估细胞向肺的募集。