Differential Roles of Chi3l1 and its receptors in COPD and IPF

摘要 COPD和特发性肺纤维化(IPF)等纤维化疾病的病理机制明显不同 前者以组织丢失为特征，后者以间质纤维化和过度基质沉积为特征。 然而，最近的研究强调了一组患有肺气肿和间质的慢性阻塞性肺病患者。 肺异常(ILA)，并表明损伤和修复在这两种疾病中起着关键作用。他们也 证明转化生长因子-β1是一种调节失调的介质，在两者中都具有惊人的推动纤维化的能力 同时增加组织损伤和细胞死亡。确定决定转化生长因子-β-1是否导致 肺气肿和/或纤维化，我们在10个近交系基因上产生了肺靶向转化生长因子-β1转基因(TG)小鼠 背景。在这些小鼠的计算机单倍型评估和表达微阵列分析中，我们有 确定了与转化生长因子-β1诱导的纤维化或肺气肿相关的基因。有趣的是，对这些转化生长因子的研究- β-1基因修饰剂均能产生几丁质酶样蛋白--几丁质酶3-样蛋白及其受体。 为了进一步了解CHI3L1轴在肺气肿和纤维化中的作用(S)，最近的研究集中在 CHI3L1及其受体的生物学研究这些研究表明：(1)CHI3L1是在 在促进修复的同时抑制损伤的损伤和修复，(2)香烟烟雾(CS)诱导的肺气肿 和博莱霉素反应，CHI3L1抑制上皮细胞死亡和组织破坏，并推动组织纤维化 CHI3L1的作用分别由两种不同的受体介导，一个称为CHI3L1的多聚体复合体 调节细胞死亡的壳体和驱动纤维增殖修复的CRTH2，(4)壳体有一个 α亚基(IL-13Rα2)和两个不同的β亚基TMEM219(TMEM)和Galectin 3(GAL3)，它们相互竞争 用TMEM结合IL-13Rα2。我们最新的研究也强调了磷酸化和非 CHI3L1的磷酸化形式，表明壳小体的成分受表观遗传调控 CHI3L1轴和线粒体之间的修饰和突出关系。这些发现导致了 本项目的总体假设：CHI3L1和CHI3L1的差异表达、利用和或磷酸化 受体在纤维化和肺气肿的不同结果的产生中起主要作用。致信地址 在这个假设中，我们将(目标1)描述纤维化相关疾病和肺气肿之间的关系。 CS暴露后肺组织相关转化生长因子-β-1基因修饰物和CHI3L1及其受体的变化 或转化生长因子-β-1，以及在纤维化和肺气肿的动物模型中，(目标2)表征位置、机制和 CHI3L1通过细胞周期蛋白依赖性激酶(CDK)、磷酸酶PP2A和 FAM13A，(目标#3)表征IL-13Rα2糖基化和IL-2的表观遗传修饰的重要性 13Rα2和TMEM在CHI3L1的运输、结合和效应反应中的作用 CHI3L1轴与线粒体的相互作用；具体地说，线粒体如何调节CHI3L1轴 以及轴如何调节线粒体的功能、动力学、生物发生、新陈代谢和有丝分裂。

ABSTRACT COPD and fibrotic disorders like idiopathic pulmonary fibrosis (IPF) have remarkably different pathologies with the former characterized by tissue loss and the latter by interstitial fibrosis and excess matrix deposition. However, recent studies highlighted a subgroup of patients with COPD with both emphysema and interstitial lung abnormalities (ILA) and demonstrated that injury and repair play critical roles in both disorders. They also demonstrated that TGF-β1 is a mediator that is dysregulated in both that has the surprising ability to drive fibrosis while augmenting tissue injury and cell death. To define the mechanisms that determine if TGF-β1 cause emphysema and or fibrosis, we generated lung-targeted TGF-β1 transgenic (Tg) mice on 10 inbred genetic backgrounds. Using In silico haplotype evaluations and expression microarray analysis on these mice, we have identified genes associated with TGF-β1-induced fibrosis or emphysema. Interestingly, the studies of these TGF- β1 genetic modifiers all led to the prototypic chitinase-like protein, chitinase 3-like-1 (Chi3l1) and its receptors. To further understand the role(s) of the Chi3l1 axis in emphysema and fibrosis, recent studies have focused on the biology of Chi3l1 and its receptors. These studies demonstrated that; (1) Chi3l1 is induced at sites of injury and repair where it inhibits injury while fostering repair, (2) In cigarette smoke (CS)-induced emphysema and bleomycin responses, Chi3l1 inhibits epithelial cell death and tissue destruction and drives tissue fibrosis respectively, (3) The effects of Chi3l1 are mediated by 2 different receptors, a multimeric complex called the chitosome that regulates cell death and CRTH2 which drives fibroproliferative repair, (4) The chitosome has one alpha subunit (IL-13Rα2) and 2 different β subunits, TMEM219 (TMEM) and galectin 3 (Gal3), which competes with TMEM for IL-13Rα2 binding. Our most recent studies have also highlighted phosphorylated and non- phosphorylated forms of Chi3l1, demonstrated that the components of the chitosome are regulated by epigenetic modifications and highlighted relationships between the Chi3l1 axis and mitochondria. These findings led to the overall hypothesis for this project: The differential expression, utilization and or phosphorylation of Chi3l1 and its receptors play major roles in the generation of the divergent outcomes of fibrosis and emphysema. To address this hypothesis, we will (Aim#1) characterize the relationships between the fibrosis-associated and emphysema- associated TGF-β1 genetic modifiers and Chi3l1 and its receptors in the lung at baseline, after exposure to CS or TGF-β1, and in animal models of fibrosis and emphysema, (Aim#2) characterize the site, mechanism and consequences of Chi3l1 activation/deactivation via cyclin-dependent kinase (CDK), the phosphatase PP2A & FAM13A, (Aim #3) characterize the importance of IL-13Rα2 glycosylation and epigenetic modifications of IL- 13Rα2 and TMEM in the trafficking, binding and effector responses of Chi3l1, (Aim #4) characterize the interactions between the Chi3l1 axis and mitochondria; specifically, how mitochondria regulate the Chi3l1 axis and how the axis regulates mitochondrial function, dynamics, biogenesis, metabolism, and mitophagy.