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

基本信息

批准号：
10554375
负责人：
Yang Zhou
金额：
$ 40.63万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10554375
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 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 Proliferating Proteins Pulmonary Fibrosis Regulation Role Severity of illness Signal Transduction System Testing Th2 Cells Therapeutic Therapeutic Effect Vesicle autosome cell injury cell motility cell type comparison control 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 prototype receptor repaired response therapeutic target trafficking

项目摘要

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 Hermansky-Pudlak综合征（HPS）是一组由遗传引起的遗传常染色体隐性疾病改变溶酶体相关细胞器/囊泡的运输的突变。在HPS-1和HPS-4的患者中亚型，肺纤维化在生命的第四或第五个十年中发展，是发病率的主要原因虽然HP是良好的遗传改变，但介导的机制是尚未阐明肺纤维化的发展。结果，可以是尚未描述被操纵以控制HP中肺纤维化的发展。几丁质酶3样1（CHI3L1）是原型几元酶样蛋白。我们实验室和其他人的研究证明HPS-1和HPS-4的个体以及其他人的CHI3L1循环水平高3倍与对照相比，肺纤维化的形式与疾病严重程度相关。我们的学习定义CHI3L1受体表明CHI3L1调节各种细胞类型的细胞损伤和修复反应通过多个受体或共受体，包括IL-13Rα2（及其共受体TMEM219）和CRTH2 （在Th2细胞上表达的趋化剂受体分子）。我们的初步研究突出了Chi3L1轴的重要性，这是促进增强纤维增生性修复的主要贡献者 HPS：1）在HPS小鼠模型的肺中，CRTH2阳性II型先天淋巴样细胞（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的激活和纤维增殖； 3）纤双（gal-3）成纤维细胞； 4）GAL-3的细胞内积累通过抑制纤维增生性修复成纤维细胞细胞凋亡以及增加成纤维细胞增殖和肌纤维细胞转化。那，附加有必要对CHI3L1及其受体在与HPS相关的肺部疾病中的作用进行研究。我们假设CHI3L1-CRTH2轴导致ILC2的积累增加，而GAL-3产生/积累在HPS肺部疾病中的成纤维细胞中，靶向该途径中的部分将导致有效的疗法。该项目提出的实验将研究肺部浅鼠模型中的CHI3L1生物学与人类HPS疾病类似的表型纤维化。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目标治疗与HPS相关的肺部疾病。此外，针对此途径可能会使患者受益于其他形式的患者肺纤维化，包括特发性肺纤维化（IPF）。