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

靶向 CHI3L1 及其受体治疗赫曼斯基-普德拉克综合征相关肺部疾病

• 批准号: 9887633
• 负责人: Yang Zhou
• 金额: $ 40.63万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9887633
• 关键词: Apoptosis; Attenuated; Biogenesis; Biology; Blood Platelets; CHI3L1 gene; Cell Death; Cells; Chitinase; Complex; Cytoplasmic Granules; DNA Sequence Alteration; Defect; Deposition; Development; Disease; Disease susceptibility; Ear; Epithelial Cells; Fibroblasts; Fibrosis; Galectin 3; Genes; Hemorrhage; Hermanski-Pudlak Syndrome; Human; Impairment; In Vitro; Individual; Inherited; Investigation; Laboratories; Lead; Life; Lung; Lung diseases; Lymphoid Cell; Mediating; Melanosomes; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myofibroblast; Oculocutaneous Albinism; Organelles; Pathway interactions; Patients; Phenotype; Pigmentation physiologic function; Predisposition; Process; Production; Proteins; Pulmonary Fibrosis; Regulation; Role; Severity of illness; Signal Transduction; System; Testing; Th2 Cells; Therapeutic; Therapeutic Effect; Vesicle; base; cell injury; cell motility; cell type; effective therapy; experimental study; fMet-Leu-Phe receptor; idiopathic pulmonary fibrosis; in vivo; indium-bleomycin; injury and repair; mortality; mouse model; neutralizing antibody; patient subsets; protective effect; receptor; repaired; response; therapeutic target; trafficking

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).

抽象的 赫曼斯基-普德拉克综合征 (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 亚型中，肺纤维化发生在四十岁或五十岁，是发病的主要原因 和死亡率。尽管 HPS 背后的遗传改变已被明确定义，但介导的机制 肺纤维化的发展尚未阐明。因此，治疗靶标可 尚未描述控制 HPS 肺纤维化发展的方法。 Chitinase 3-like 1(CHI3L1) 是原型几丁质酶样蛋白。我们实验室和其他实验室的研究 证明患有 HPS-1 和 HPS-4 以及其他疾病的个体中 CHI3L1 的循环水平高出 3 倍 与对照组相比，肺纤维化的形式以及它们与疾病严重程度相关。我们的研究是为了 定义 CHI3L1 受体揭示 CHI3L1 调节各种细胞类型的细胞损伤和修复反应 通过多种受体或辅助受体，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 轴作为增强纤维增殖修复的主要贡献者的重要性 HPS：1) HPS 小鼠模型肺部 CRTH2 阳性 II 型先天淋巴细胞 (ILC2) 增加 肺纤维化； 2) CHI3L1 与 CRTH2 在这些细胞上的相互作用介导成纤维细胞活化 纤维增殖； 3) 纤维化的发生是由于 Galectin-3 依赖于 BLOC-3 的运输缺陷造成的 (Gal-3) 在成纤维细胞中； 4) Gal-3 的细胞内积累通过抑制来驱动纤维增殖修复 成纤维细胞凋亡以及增加成纤维细胞增殖和肌成纤维细胞转化。因此，额外的 有必要研究 CHI3L1 及其受体在 HPS 相关肺部疾病中的作用。我们 假设 CHI3L1-CRTH2 轴导致 ILC2 积累和 Gal-3 产生/积累增加 HPS 肺病的成纤维细胞中存在这种信号通路，针对该通路中的部分将产生有效的治疗方法。 该项目提出的实验将研究苍耳小鼠肺模型中的 CHI3L1 生物学 纤维化的表型与人类 HPS 疾病相似。这些研究将定义细胞和分子 CHI3L1 受体系统的机制，以及 CHI3L1 及其受体系统是否是合理的靶点 治疗 HPS 相关的肺部疾病。此外，针对这一途径可能有益于患有其他形式的患者 肺纤维化，包括特发性肺纤维化(IPF)。