CHI3L1 and its Receptors in Vascular Remodeling and Pulmonary Hypertension Associated with Pulmonary Fibrosis

CHI3L1 及其受体在与肺纤维化相关的血管重塑和肺动脉高压中的作用

基本信息

批准号：
9573405
负责人：
Yang Zhou
金额：
$ 25.63万
依托单位：
OCEAN STATE RESEARCH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9573405
关键词：
Affect Animal Model Apoptosis Architecture Binding Biology Bleomycin Blood Vessels CHI3L1 gene Cardiopulmonary Cell Death Cell Proliferation Cells Centers of Research Excellence Chitinase Complex Deposition Development Diagnosis Disease Disease Progression Endothelial Cells Epithelial Cells Extracellular Matrix Fibroblasts Fibrosis Functional disorder Galectin 3 Human Impairment Individual Inflammation Injury Knockout Mice Laboratories Lung Lung diseases Macrophage Activation Mediating Medical Mus Organ Patients Phenotype Play Proteins Pulmonary Fibrosis Pulmonary Hypertension Respiratory physiology Role Severity of illness Signal Transduction Smooth Muscle Myocytes System Testing Therapeutic Therapeutic Effect Tissues Transgenic Animals Transgenic Mice United States Vascular Endothelial Cell Vascular remodeling Vasodilator Agents antibody inhibitor base cancer type cell injury cell type experimental study human disease idiopathic pulmonary fibrosis indium-bleomycin injury and repair mortality mouse model neutralizing antibody new therapeutic target novel therapeutics outcome forecast overexpression receptor repaired response vascular abnormality

项目摘要

Pulmonary fibrosis affects millions of people worldwide. A common form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The mean survival after diagnosis is only approximately 3 years, which is similar to, if not worse than, the prognosis associated with many types of cancer. IPF is characterized by epithelial and endothelial cell damage, varying degrees of inflammation, abnormal pulmonary vascular remodeling, aberrant fibroblast proliferation, and extracellular matrix deposition that result in distortion of pulmonary architecture and organ dysfunction. The development of pulmonary hypertension (PH) in settings of IPF occurs in 60-80% of patients and predicts mortality from the disease. However, the mechanisms that drive endothelial injury, abnormal vascular remodeling, and the development of PH are poorly understood, and currently available therapies that act as pulmonary vasodilators have failed to be beneficial in IPF patients. Therefore, novel therapeutic targets that can be manipulated to control the vascular remodeling and PH in these disorders are in dire need of scientific breakthroughs. Chitinase 3-like 1(CHI3L1) is the prototypic chitinase-like protein. The levels of circulating CHI3L1 levels are higher in individuals with IPF and other forms of pulmonary fibrosis compared to controls and that they correlate with disease severity. CHI3L1 has multiple effects in the lung where it plays a protective role in tissue damage by ameliorating epithelial cell death, and a pro-fibrotic role via its ability to stimulate alternative (M2) macrophage activation, fibroblast proliferation and matrix deposition. These divergent responses are mediated by distinct receptor systems in various cell types. However, despite its importance as a regulator of injury/repair responses in pulmonary fibrosis, the interrelationship between CHI3L1 and vascular repair/remodeling associated with pulmonary fibrosis has never been investigated, and the receptor complexes through which CHI3L1 mediates different effector responses in vascular cells have not been characterized. In preliminary studies, we found that pulmonary hypertensive responses during the development of pulmonary fibrosis were mitigated in CHI3L1 null mice and accentuated in transgenic mice that overexpress CHI3L1. We hypothesize that the CHI3L1 and its receptors modulate abnormal pulmonary vascular remodeling and the development of PH in pulmonary fibrosis. We propose to 1) define the cellular effects of CHI3L1 and its receptors on vascular endothelial cells and smooth muscle cells; 2) determine the role of CHI3L1 and its receptors in vascular remodeling and PH in the well-characterized bleomycin mouse model of pulmonary fibrosis; 3) develop CHI3L1-based therapeutics to treat vascular remodeling and PH associated with pulmonary fibrosis. The proposed studies will determine the role of CHI3L1 signaling in pulmonary vascular cells, and may reveal new therapeutic options to slow the development of PH in IPF.

肺纤维化影响着全世界数百万人。肺纤维化的一种常见形式是特发性肺纤维化（IPF）。诊断后的平均生存期仅为大约 3 年，这与如果并不比与多种癌症相关的预后更差。 IPF 的特点是上皮细胞和内皮细胞损伤、不同程度的炎症、肺血管重塑异常、异常成纤维细胞增殖和细胞外基质沉积导致肺结构扭曲器官功能障碍。 60-80% 的 IPF 患者会出现肺动脉高压 (PH) 患者并预测该疾病的死亡率。然而，驱动内皮损伤的机制，对异常血管重塑和 PH 的发展知之甚少，目前可用作为肺血管扩张剂的疗法未能对 IPF 患者有益。因此，小说可以操纵来控制这些疾病中的血管重塑和 PH 的治疗靶点正在研究中。迫切需要科学突破。 Chitinase 3-like 1(CHI3L1) 是原型几丁质酶样蛋白。循环 CHI3L1 水平为与对照组相比，患有 IPF 和其他形式肺纤维化的个体的这一比例更高，而且他们与疾病严重程度相关。 CHI3L1 在肺部具有多种作用，在组织中发挥保护作用通过改善上皮细胞死亡来减轻损伤，并通过刺激替代 (M2) 的能力发挥促纤维化作用巨噬细胞活化、成纤维细胞增殖和基质沉积。这些不同的反应是经过调解的通过不同细胞类型中不同的受体系统。然而，尽管它作为监管者的重要性肺纤维化损伤/修复反应，CHI3L1与血管之间的相互关系与肺纤维化相关的修复/重塑从未被研究过，并且受体复合物 CHI3L1 通过何种方式介导血管细胞中的不同效应反应尚未得到表征。在初步研究，我们发现肺动脉高压反应发生在肺动脉高压的发展过程中。纤维化在 CHI3L1 缺失小鼠中减轻，而在过表达 CHI3L1 的转基因小鼠中加剧。我们假设 CHI3L1 及其受体调节异常的肺血管重塑肺纤维化中PH的发展。我们建议 1) 定义 CHI3L1 及其细胞效应血管内皮细胞和平滑肌细胞上的受体； 2) 确定CHI3L1及其作用博来霉素小鼠肺模型中血管重塑和 PH 受体的研究纤维化； 3) 开发基于 CHI3L1 的疗法来治疗与以下疾病相关的血管重塑和 PH 肺纤维化。拟议的研究将确定 CHI3L1 信号在肺血管中的作用细胞，并可能揭示减缓 IPF PH 发展的新治疗选择。