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

摘要 Hermansky-Pudlak综合征（HPS）是一组由遗传因素引起的常染色体隐性遗传疾病， 改变溶酶体相关细胞器/囊泡运输的突变。HPS-1和HPS-4患者 亚型，肺纤维化在生命的第四或第五个十年中发展，并且是发病的主要原因 and mortality.虽然HPS的遗传改变已经被很好地定义，但介导HPS的机制仍然是未知的。 肺纤维化的发展尚未阐明。因此，可以作为治疗靶点， 用于控制HPS中肺纤维化发展的方法尚未被描述。 几丁质酶3-样1（CHI 3L 1）是原型几丁质酶样蛋白。我们实验室和其他机构的研究 研究表明，在HPS-1和HPS-4个体中，CHI 3L 1的循环水平高3倍，而其他 与对照组相比，肺纤维化的形式，并且它们与疾病的严重程度相关。我们的研究， 定义CHI 3L 1受体揭示了CHI 3L 1调节各种细胞类型中的细胞损伤和修复反应 通过多种受体或共受体，包括IL-13 R α2（及其共受体TMEM 219）和CRTH 2 （在Th 2细胞上表达的化学引诱物受体同源分子）。我们的初步研究进一步 强调了CHI 3L 1轴作为增强纤维增生修复的主要贡献者的重要性， HPS：1）CRTH 2阳性II型先天淋巴样细胞（ILC 2）在HPS小鼠模型的肺中增加 2）CHI 3L 1与CRTH 2在这些细胞上的相互作用介导成纤维细胞活化， 纤维化的发展是由于半乳糖凝集素-3的缺陷BLOC-3依赖性运输 （Gal-3）在成纤维细胞中的细胞内积累;和4）Gal-3的细胞内积累通过抑制纤维增生性修复驱动纤维增生性修复。 成纤维细胞凋亡和增加成纤维细胞增殖和肌成纤维细胞转化。由此具有附加 研究CHI 3L 1及其受体在HPS相关性肺病中的作用是必要的。我们 假设CHI 3L 1-CRTH 2轴导致ILC 2积累和Gal-3产生/积累增加 在HPS肺病的成纤维细胞中，靶向该途径中的部分将导致有效的治疗。 本项目中提出的实验将研究CHI 3L 1在白耳小鼠模型中的生物学， 与人类HPS疾病表型相似的纤维化。这些研究将确定细胞和分子 CHI 3L 1受体系统的机制，以及CHI 3L 1及其受体系统是否是合理的目标， 治疗HPS相关的肺部疾病。此外，靶向这一途径可能有益于其他形式的糖尿病患者。 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).