Targeting CHI3L and its receptors in Hermansky-Pudlak Syndrome-associated lung disease

靶向 CHI3L 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: 10850273
• 负责人: Yang Zhou
• 金额: $ 4.47万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10850273
• 关键词: Apoptosis; Biology; Cells; Chitinase; DNA Sequence Alteration; Development; Disease; Ear; Fibroblasts; Fibrosis; Galectin 3; Hermanski-Pudlak Syndrome; Human; Individual; Inherited; Investigation; Laboratories; Life; Lung; Lung diseases; Lymphoid Cell; Mediating; Molecular; Morbidity - disease rate; Mutation; Myofibroblast; Organelles; Pathway interactions; Patients; Phenotype; Production; Proliferating; Proteins; Pulmonary Fibrosis; Role; Severity of illness; System; Th2 Cells; Vesicle; autosome; cell injury; cell type; comparison control; effective therapy; experimental study; fMet-Leu-Phe receptor; idiopathic pulmonary fibrosis; injury and repair; mortality; mouse model; parent project; patient subsets; prototype; receptor; repaired; response; therapeutic target; trafficking

Summary of the Parent Project 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. Chtinase 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).

父项目摘要 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 HPS-1 和 HPS-4 患者溶酶体相关细胞器/囊泡运输的突变。 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 尽管 HPS 背后的遗传改变已经明确，但介导的机制却很明确。 因此，肺纤维化的发展尚未阐明。 尚未描述控制 HPS 肺纤维化发展的方法。 Chtinase 3-like 1(CHI3L1) 是我们实验室和其他实验室研究的原型几丁质酶样蛋白。 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的相关性。 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）。 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和 纤维增殖；3) 纤维化的发生是由于 Galectin-3 的 BLOC-3 依赖性运输缺陷所致 (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 成纤维细胞凋亡并通过增加成纤维细胞增殖和肌成纤维细胞转化而增加。 有必要研究 CHI3L1 及其受体在 HPS 相关肺部疾病中的作用。 CHI3L1-CRTH2 轴增加导致 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病模型中的 CHI3L1 生物学 这些研究将定义与人类 HPS 疾病表型相似的纤维化的细胞和分子。 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 此外，针对这一途径可能会使患有其他形式的肺部疾病的患者受益。 肺纤维化包括特发性肺纤维化（IPF）。