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Genetic Factors Controlling Effector Function of TGF-beta in COPD and Fibrosis

控制 COPD 和纤维化中 TGF-β 效应器功能的遗传因素

基本信息

批准号：
7326828
负责人：
CHUN GEUN LEE
金额：
$ 41.3万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-05 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7326828
关键词：
Address Alveolus Animal Model Animals Apoptosis Apoptotic Arginine Biological Markers Breeding Candidate Disease Gene Cathepsins Cationic Amino Acid Transporter 2 Chemicals Chronic Obstructive Airway Disease Cicatrix Collaborations Collagen Computer Analysis Computer Simulation DNA Repair Development Elastin Enzymes Epithelial Cells Equilibrium Evaluation Family member Fibronectins Fibrosis Generations Genes Genetic Haplotypes Histologic Human In Situ Nick-End Labeling Inflammation Inflammatory Injury Institutes Intervention Knockout Mice Laminin Lesion Literature Lung Maps Matrix Metalloproteinases Medical Messenger RNA Molecular Mus Myofibroblast NOS1 protein, human Nitric Oxide Synthase Ornithine Ornithine Decarboxylase Outcome Pathogenesis Patients Phenotype Production Protease Inhibitor Protein Overexpression Protein-Lysine 6-Oxidase Proteins Proteolysis Pulmonary Emphysema Pulmonary Fibrosis Quantitative Trait Loci Research Personnel Role Screening procedure Signal Transduction Staging Staining method Stains Structure of parenchyma of lung System Tissues Transferase Transforming Growth Factor beta Transforming Growth Factors Transgenic Animals Transgenic Mice Transgenic Organisms Universities alveolar destruction arginase base cytokine inhibitor/antagonist matrix metalloproteinase 12 medical schools novel programs protein expression repaired response

项目摘要

Alveolar destruction and pulmonary fibrosis are juxtaposed in COPD and pulmonary fibrosis. Surprisingly, the relationships between these responses and the mechanisms that destroy alveoli while simultaneously nducing fibrosis have not been defined. Transforming Growth Factor-betal (TGF-b1) is expressed in an exaggerated fashion in COPD and pulmonary fibrosis and TGF-b1 abnormalities have been implicated in the pathogenesis of emphysema and scarring. The mechanisms that TGF-b1 uses to induce these different outcomes and the genetic factors that control these divergent responses have not been investigated. We developed novel triple transgenic mice overexpressing bioactive TGF-b1 in the murine lung. In 57BL/6 mice this TGF-b1 caused epithelial cell apoptosis, pulmonary fibrosis and honeycombing. In contrast, in Balb/c mice TGF-b1 caused emphysema with minimal tissue fibrosis. Exaggerated apoptosis and matrix metalloproteinase-12 induction were seen in Balb/c animals and prominent stimulation of lysyl oxidase, arginase II and Cyr-61 were seen in C57BL/6 animals. This led to the following hypothesis: 1. TGF-b1 is a multifunctional cytokine that simultaneously induces tissue injury and fibrosis and generates emphysematous and/or fibrotic phenotypes. 2. The tissue effects of TGF-b1 depend, in part, on the balance of apoptosis, proteolysis and fibrosis. 3. The ability of TGF-b1 to induce these divergent phenotypes is determined by definable TGF-b1 effector function regulating genes. To address this hypothesis, we propose to: AIM #1. Generate and characterize inducible, lung-targeted TGF-b1 overexpressing (OE) transgenic mice on C57BL/6 and Balb/c genetic backgrounds. AIM #2. Characterize the mechanisms that contribute to the different phenotypes that are induced by TGF- b1 in C57BL/6 and Balb/c transgenic animals. AIM #3. Characterize the roles of the arginase system in the generation of the TGF-b1-induced phenotypes in C57BL/6 and Balb/c transgenic mice. AIM #4. Define the genes that determine whether TGF-b1 induceds a predominantly fibrotic versus emphysematous response in C57BL/6 and Balb/c mice.

肺泡破坏和肺纤维化在COPD和肺纤维化中是并列的。令人惊奇的是，这些反应与破坏肺泡同时的机制之间的关系导致纤维化的原因尚未确定。转化生长因子-β 1（TGF-β 1）表达于 COPD和肺纤维化的夸大方式和TGF-β 1异常已经被牵连，肺气肿和瘢痕形成的发病机制。TGF-β 1诱导这些不同的细胞分化的机制，结果和控制这些不同反应的遗传因素尚未研究。我们开发了新的三重转基因小鼠在小鼠肺中过表达生物活性TGF-β 1。在 57 BL/6小鼠肺组织中TGF-β 1的表达可引起上皮细胞凋亡、肺纤维化和蜂窝样改变。在相反，在Balb/c小鼠中，TGF-β 1引起肺气肿，伴有最小的组织纤维化。过度的细胞凋亡和在Balb/c动物中观察到基质金属蛋白酶-12诱导，赖氨酰在C57 BL/6动物中观察到氧化酶、脱氢酶II和Cyr-61。这导致了以下假设： 1. TGF-β 1是一种多功能细胞因子，可同时诱导组织损伤和纤维化，产生肺气肿和/或纤维化表型。 2. TGF-β 1的组织效应部分取决于细胞凋亡、蛋白水解和纤维化的平衡。 3. TGF-β 1诱导这些不同表型的能力由可定义的TGF-β 1 效应子功能调节基因。为了解决这一假设，我们建议：目标1。产生和表征诱导型、肺靶向TGF-β 1过表达（OE）转基因小鼠， C57 BL/6和Balb/c遗传背景。目标#2。表征有助于由TGF-β 1诱导的不同表型的机制。在C57 BL/6和Balb/c转基因动物中的b1。目标#3。描述TGF-β 1诱导的表型产生过程中，TGF-β 1酶系统的作用在C57 BL/6和Balb/c转基因小鼠中。目标#4.定义决定TGF-β 1是否诱导主要纤维化的基因， C57 BL/6和Balb/c小鼠的肺气肿反应。