Pathophysiology of PPARgamma in the lung

肺部 PPARγ 的病理生理学

• 批准号: 7523431
• 负责人: HONG DU
• 金额: $ 37.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-09 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7523431
• 关键词: 9-hydroxy-10,12-octadecadienoic acid; Acid Lipase; Acids; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arts; Attenuated; Biological Assay; Cell Adhesion Molecules; Cells; Chronic Obstructive Airway Disease; Clara cell; Complex; Development; Dominant-Negative Mutation; Doxycycline; Enzymes; Epithelial; Epithelial Cells; Fatty Acids; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Goals; Human; In Vitro; Inflammation; Inflammatory; Injury; Knock-out; Knowledge; Ligands; Lung; Lung diseases; Lysosomes; Mediating; Mediator of activation protein; Molecular; Mus; Outcome Study; PPAR gamma; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Pneumonia; Proteins; Pulmonary Emphysema; Regulation; Regulatory Element; Research Proposals; Role; Stream; System; Techniques; Testing; Tissues; Transcriptional Regulation; Transfection; Transgenic Mice; Transgenic Model; Work; alveolar type II cell; c-fms Proto-Oncogenes; cell growth; chemokine; ciglitazone; cytokine; design; enzyme activity; lung development; macrophage; matrix metalloproteinase 12; novel strategies; promoter; repaired; respiratory; transcription factor

DESCRIPTION (provided by applicant): Peroxisome proliferator-activated receptor gamma (PPAR() is an anti-inflammatory molecule in various tissue systems including the lung. Its functional role in the lung is not well understood. The long-term goal of this work will determine PPAR( molecular pathways in lung pathogenesis. The central hypothesis for the proposed studies is that PPAR( is a mediator of pulmonary inflammation via the molecular control of matrix metalloproteinase-12 (MMP-12) and that this control derives from fatty acid ligands, generated in the lysosomes by lysosomal acid lipase (LAL). This has been supported by our previous study that blockage of its ligand synthesis in lysosomal acid lipase deficient mice (lal-/-) caused pulmonary inflammation, emphysema, unwanted epithelial cell growth and aberrant gene expression. Treatment with PPAR( ligands 9-HODE and Ciglitazone significantly attenuated lal-/- pulmonary inflammation and aberrant gene expression. The ligands and PPAR( negatively regulate MMP-12 promoter activity in in vitro transient transfection assays. The PPAR( protein is primarily detected in broncho-alveolar macrophages, Clara cells and alveolar type II epithelial cells in the lung. Thus, the central hypothesis will be tested in our two new transgenic models, in which endogenous PPAR( is inactivated by over-expression of its dominant negative form (dnPPAR() in alveolar type II epithelial cells or bronchoalveolar macrophages in doxycycline-inducible transgenic mouse system. Preliminary assessment of a transgenic model, in which dnPPAR( was over- expressed for 2 months under the control of the CCSP promoter, showed inflammatory cell influx into the lung and emphysema. In addition, the expression level of MMP12 increased 55-fold in the dnPPAR( transgenic mice. The long-term pathogenic effect of dnPPAR( over-expression has not been determined. Three specific aims are designed to test the central hypothesis: Specific Aim 1: Determine pathogenesis of dnPPAR( in respiratory epithelial cells; Specific Aim 2: Determine pathogenesis of dnPPAR( in macrophages; Specific Aim 3: Determine molecular mechanism of MMP12 regulation in lung epithelial cells. Together, these studies will significantly enhance our knowledge for understanding the pathophysiological function of PPAR( in the lung, especially in pulmonary inflammation and tissue remodeling, and elucidate the molecular mechanism of gene regulation in MMP12 that mediates the phenotype in the lung of lal-/- mice. The outcomes of these studies will provide evidence to design new strategies to combat pulmonary inflammation and emphysema. PROJECT NARRATIVE: The objectives of this research proposal are to understand the critical role of peroxisome proliferator- activated receptor gamma (PPAR() as anti-inflammatory effector in the lung. We are using the state-of-art techniques to create transgenic mice that have cell specific and temporal regulated expression of dominant negative form of PPAR( (dnPPAR() in pulmonary cells (alveolar type II epithelial cells or bronchio-alveolar macrophages) and characterizing their pulmonary inflammation, remodeling, and emphysema phenotype. In addition, the proposed studies will elucidate the molecular linker of inactivation of PPAR( and the remodeling and emphysema phenotype through transcriptional regulation of matrix metallproteinase-12 (MMP-12) gene. Together, these studies will significantly enhance our knowledge for understanding the pathophysiological function of PPAR( in the lung, especially in pulmonary inflammation and tissue remodeling. These studies will provide new approaches to design strategies and discover drugs to combat emphysema and COPD.

描述（由申请人提供）：过氧化物酶体增殖物激活的受体γ（PPAR（PPAR（）是包括肺在内的各种组织系统中的抗炎分子。其在肺中的功能作用尚不很好地理解。该工作的长期目标将通过肺发病机构的pPAR（分子途径）的长期目标。 molecular control of matrix metalloproteinase-12 (MMP-12) and that this control derives from fatty acid ligands, generated in the lysosomes by lysosomal acid lipase (LAL). This has been supported by our previous study that blockage of its ligand synthesis in lysosomal acid lipase deficient mice (lal-/-) caused pulmonary inflammation, emphysema,上皮细胞的生长和异常基因表达。 The PPAR( protein is primarily detected in broncho-alveolar macrophages, Clara cells and alveolar type II epithelial cells in the lung. Thus, the central hypothesis will be tested in our two new transgenic models, in which endogenous PPAR( is inactivated by over-expression of its dominant negative form (dnPPAR() in alveolar type II epithelial cells or bronchoalveolar macrophages在强力霉素诱导的转基因小鼠系统中。尚未确定过表达的三个特定目的是为了测试中心假设：具体目标1：确定DNPPAR的发病机理（在呼吸上皮细胞中；具体目标2：确定DNPPAR的发病机理（巨噬细胞；具体目标3：确定肺上皮细胞中MMP12调节的分子机制。总之，这些研究将显着增强我们的知识，以理解PPAR的病理生理功能（在肺部，尤其是在肺部炎症和组织中，并阐明了MMP12中基因调节的分子机制，这些基因调节的分子机制介导了LAL - / - / - 小鼠的肺部疾病中的表型。叙述：这项研究建议的目标是了解过氧化物酶体增生剂激活受体伽马（PPAR（PPAR（）作为肺中的抗炎效应子）。我们正在使用最先进的技术来创建具有细胞特异性和时间调节PPAR（DNPPARY eply eply eply eply eply eply eply eply eply eply eply eply comp ppar）（dnply eply eply eply conse coldy conse conse conse）的转基因小鼠（）（）支气管 - 肺泡巨噬细胞）并表征其肺部炎症，重塑和肺气肿表型，此外，提出的研究将阐明PPAR失活的分子接头（以及通过重塑和振动性表型通过基质化金属酶-12（MMPPPPPPPPPPPPPPPP）的转录和孔径表型。总之，这些研究将显着增强我们的知识，以理解PPAR的病理生理功能（在肺部，尤其是在肺部炎症和组织重塑中。这些研究将为设计策略提供新的方法，并发现药物以对抗肺气肿和COPD。