Resistin-like molecules in pulmonary fibrosis

肺纤维化中的抵抗素样分子

基本信息

批准号：
8420737
负责人：
SEM H PHAN
金额：
$ 48.04万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8420737
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

项目摘要

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（由适用提供）：慢性进行性纤维化肺部疾病，例如特发性肺纤维化，基本上无法治疗，迫切需要阐明机制以帮助发现新型有效治疗。这些疾病涉及内源性肺和骨髓之间通过无数介质衍生细胞之间的复杂而复杂的相互作用，尚未确定其完整光谱。 relm¿（抗蛋白样分子¿）/fizz1（在炎症区域1中发现），最近发现，抵抗素分子家族的成员在肺纤维化动物模型中被高度诱导，并证明可以激活成纤维细胞，并通过促进肌纤维细胞区分并增强对凋亡刺激的抵抗力。它主要由肺上皮细胞表达，这可以通过STAT6诱导Th2细胞因子诱导。这些元素在小鼠中的缺乏会降低与肺纤维化减少相关的肺部。尽管有暗示性的证据表明在纤维化中发挥作用，但RELM纤维化中的确切体内作用仍不清楚。这该项目的中心假设是Relmâ及其同源第二个家庭成员Relm¿ /Fizz2在肺部损伤过程中被诱导在上皮细胞中，从而激活相邻成纤维细胞和促肌纤维细胞分化，并参与募集O骨髓衍生的细胞。这些介体引发的这些细胞元素之间的相互作用导致纤维化及其进展。 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 recruiting and consequent impact on fibrosis, 3) identify their cellular receivers, primary downstream signaling pathways and regulated target genes, and 4) examine the regulation of RELM¿ gene expression in lung type II肺泡上皮细胞。这些方法将探索生化和分子工具的组合，以剖析与其表达相关的分子机制，并将使用已经可用的转基因鼠菌株来确认其在体内的重要性。骨髓嵌合体小鼠将用于评估肺部细胞募集。