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

描述(申请人提供)：肺泡破坏和肺纤维化并存于慢性阻塞性肺疾病和肺纤维化。令人惊讶的是，这些反应与破坏肺泡同时诱导纤维化的机制之间的关系尚未确定。转化生长因子-β1(TGF-β1)在慢性阻塞性肺疾病(COPD)和肺纤维化中以过度表达的方式表达，转化生长因子-β1的异常参与了肺气肿和瘢痕形成的发病机制。转化生长因子-1诱导这些不同结果的机制以及控制这些不同反应的遗传因素尚未被研究。我们建立了新的三重转基因小鼠，在小鼠肺内过表达具有生物活性的转化生长因子-1。在57BL/6小鼠中，这种转化生长因子-1可引起肺上皮细胞凋亡、肺纤维化和蜂窝状改变。相比之下，在Balb/c小鼠中，转化生长因子-1(1)导致肺气肿，组织纤维化程度最低。Balb/c小鼠出现过度的细胞凋亡和基质金属蛋白酶-12诱导，C57BL/6小鼠出现明显的赖氨酸氧化酶、精氨酸酶II和Cyr-61的刺激。这导致了以下假设：1.转化生长因子-β1是一种多功能细胞因子，同时诱导组织损伤和纤维化，并产生肺气肿和/或纤维化表型。2.转化生长因子-1的组织效应部分依赖于细胞凋亡、蛋白降解和纤维化之间的平衡。3.转化生长因子-1诱导这些不同表型的能力由可定义的转化生长因子-1效应功能调节基因决定。为了解决这一假设，我们建议：目的1-在C57BL/6和Balb/c遗传背景上建立并鉴定可诱导的、肺靶向的转化生长因子-(1)过表达(OE)转基因小鼠。目的2-研究转化生长因子-(1)在C57BL/6和Balb/c转基因动物中诱导不同表型的机制。目的3-研究精氨酸酶系统在C57BL/6和Balb/c转基因小鼠转化生长因子-1诱导表型形成中的作用。目的4-确定决定转化生长因子-1是否在C57BL/6和Balb/c小鼠中诱导以纤维化和肺气肿为主的反应的基因。

DESCRIPTION (provided by applicant): 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 inducing fibrosis have not been defined. Transforming Growth Factor-beta 1 (TGF-(1) is expressed in an exaggerated fashion in COPD and pulmonary fibrosis and TGF-(1 abnormalities have been implicated in the pathogenesis of emphysema and scarring. The mechanisms that TGF-(1 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-(1 in the murine lung. In 57BL/6 mice this TGF-(1 caused epithelial cell apoptosis, pulmonary fibrosis and honeycombing. In contrast, in Balb/c mice TGF-(1 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-(1 is a multifunctional cytokine that simultaneously induces tissue injury and fibrosis and generates emphysematous and/or fibrotic phenotypes. 2. The tissue effects of TGF-(1 depend, in part, on the balance of apoptosis, proteolysis and fibrosis. 3. The ability of TGF-(1 to induce these divergent phenotypes is determined by definable TGF-(1 effector function regulating genes. To address this hypothesis, we propose to: Aim 1 - Generate and characterize inducible, lung-targeted TGF-(1 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-(1 in C57BL/6 and Balb/c transgenic animals. Aim 3 - Characterize the roles of the arginase system in the generation of the TGF-(1-induced phenotypes in C57BL/6 and Balb/c transgenic mice. Aim 4 - Define the genes that determine whether TGF-(1 induces a predominantly fibrotic versus emphysematous response in C57BL/6 and Balb/c mice.