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

描述（由申请方提供）：肺泡破坏和肺纤维化在COPD和肺纤维化中并列。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β 1（TGF-β 1）在COPD和肺纤维化中以夸张的方式表达，TGF-β 1异常与肺气肿和瘢痕形成的发病机制有关。TGF-β 1用于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研究。我们开发了新型的三重转基因小鼠，在小鼠肺中过表达生物活性TGF-β 1。在57 BL/6小鼠中，这种TGF-β 1引起上皮细胞凋亡、肺纤维化和蜂窝形成。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。在Balb/c动物中观察到夸大的细胞凋亡和基质金属蛋白酶-12诱导，并且在C57 BL/6动物中观察到赖氨酰氧化酶、脱氢酶II和Cyr-61的显著刺激。这导致了以下假设：1。TGF-β 1是一种多功能细胞因子，它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. 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是由可确定的TGF-β 1效应子功能调节基因决定的。为了解决这一假设，我们提出：目的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。目的2 -在C57 BL/6和Balb/c转基因动物中，表征促成TGF-β 1诱导的不同表型的机制。目的3 -在C57 BL/6和Balb/c转基因小鼠中，鉴定TGF-β 1诱导的表型的产生中，TGF-β 1抑制酶系统的作用。目的4 -确定决定TGF-β 1是否在C57 BL/6和Balb/c小鼠中诱导主要纤维化反应与肺气肿反应的基因。

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.