Targeting CHI3L1 and its receptors in Hermansky-Pudlak Syndrome-associated lung disease

摘要 Hermansky-Pudlak综合征(HPS)是一组遗传性常染色体隐性遗传性疾病，由遗传性 改变溶酶体相关细胞器/囊泡运输的突变。感染HPS-1和HPS-4的患者 亚型，肺纤维化发生在生命的第四或第五个十年，是发病的主要原因。 和死亡率。尽管HPS背后的基因改变已经被很好地定义，但调节 肺纤维化的发展尚未阐明。因此，治疗目标可以是 HPS中控制肺纤维化发展的操作尚未被描述。 几丁质酶3样蛋白1(CHI3L1)是几丁质酶样蛋白的原型。来自我们实验室和其他实验室的研究 表明HPS-1和HPS-4携带者的循环CHI3L1水平是其他患者的3倍 肺纤维化的形式与对照组相比，它们与疾病的严重程度相关。我们的学习是为了 定义CHI3L1受体表明CHI3L1在不同类型的细胞中调节细胞损伤和修复反应 通过多个受体或辅助受体，包括IL-13Rα2(及其辅助受体TMEM219)和CRTH2 (Th2细胞上表达的趋化受体同源分子)。我们的初步研究进一步 强调CHI3L1轴作为增强的纤维增生性修复的主要贡献者的重要性 HPS：1)HPS模型小鼠肺内CRTH2阳性的II型固有淋巴样细胞(ILC2s)增多 CHI3L1与CRTH2在这些细胞上的相互作用介导成纤维细胞的活化和 纤维增殖；3)纤维化的发展是由于依赖Galectin-3的BLOC-3缺陷运输所致 (Gal-3)在成纤维细胞中的表达；4)Gal-3在细胞内的积聚通过抑制纤维增殖性修复 通过促进成纤维细胞增殖和肌成纤维细胞转化来促进成纤维细胞的凋亡。因此，额外的 有必要研究CHI3L1及其受体在HPS相关性肺部疾病中的作用。我们 假设CHI3L1-CRTH2轴导致ILC2积聚增加，Gal-3产生/积聚 在HPS肺病的成纤维细胞中，靶向这一途径的部分将导致有效的治疗。 本项目中提出的实验将研究CHI3L1在苍白耳小鼠肺疾病模型中的生物学 表型类似于人类幽门螺杆菌病的纤维化。这些研究将定义细胞和分子 CHI3L1受体系统的作用机制以及CHI3L1及其受体系统是否是靶点 治疗幽门螺杆菌相关性肺部疾病。此外，靶向这一途径可能会使患有其他形式的 肺纤维化包括特发性肺纤维化(IPF)。

Abstract Hermansky-Pudlak Syndrome (HPS) is a group of inherited autosomal recessive disorders caused by genetic mutations that alter the trafficking of lysosomal-related organelles/vesicles. In patients with HPS-1 and HPS-4 subtypes, pulmonary fibrosis develops in the fourth or fifth decade of life, and is the major cause of morbidity and mortality. Although the genetic alterations that underlie HPS are well defined, the mechanisms that mediate the development of pulmonary fibrosis have not been elucidated. As a result, therapeutic targets that can be manipulated to control the development of pulmonary fibrosis in HPS have not been described. Chitinase 3-like 1(CHI3L1) is the prototypic chitinase-like protein. Studies from our laboratory and others demonstrated that circulating levels of CHI3L1 are 3-fold higher in individuals with HPS-1 and HPS-4, and other forms of pulmonary fibrosis compared to controls and that they correlate with disease severity. Our studies to define CHI3L1 receptors revealed that CHI3L1 regulates cellular injury and repair responses in various cell types via multiple receptors or co-receptors, including IL-13Rα2 (and its co-receptor TMEM219), and CRTH2 (Chemoattractant Receptor-homologous molecule expressed on Th2 cells). Our preliminary studies further highlight the importance of the CHI3L1 axis as a major contributor to the augmented fibroproliferative repair in HPS: 1) CRTH2-positive Type II innate lymphoid cells (ILC2s) are increased in the lungs of HPS mouse models of lung fibrosis; 2) the interaction of CHI3L1 with CRTH2 on these cells mediates fibroblast activation and fibroproliferation; 3) the development of fibrosis is due to defective BLOC-3 dependent trafficking of Galectin-3 (Gal-3) in fibroblasts; and 4) intracellular accumulation of Gal-3 drives fibroproliferative repair by inhibiting fibroblast apoptosis and by increasing fibroblast proliferation and myofibroblast transformation. Thus, additional investigations of the roles of CHI3L1 and its receptors in HPS-associated lung disease are warranted. We hypothesize that CHI3L1-CRTH2 axis leads to increased ILC2 accumulation, and Gal-3 production/accumulation in fibroblasts in HPS lung disease, and that targeting the moieties in this pathway will result in effective therapies. Experiments proposed in this project will investigate CHI3L1 biology in pale ear mouse models of pulmonary fibrosis with phenotypes similar to human HPS disease. These studies will define the cellular and molecular mechanisms of CHI3L1 receptor system, and whether CHI3L1 and its receptor systems are plausible targets to treat HPS-associated lung disease. In addition, targeting this pathway may benefit patients with other forms of pulmonary fibrosis including Idiopathic Pulmonary Fibrosis (IPF).