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

• 批准号: 10437834
• 负责人: Yang Zhou
• 金额: $ 6.47万
• 依托单位: OCEAN STATE RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2022-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437834
• 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; Endothelium; 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; Persons; Phenotype; Play; Prognosis; Proteins; Pulmonary Fibrosis; Pulmonary Hypertension; 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; fibrotic lung; human disease; hypertensive; idiopathic pulmonary fibrosis; indium-bleomycin; injury and repair; mortality; mouse model; neutralizing antibody; new therapeutic target; novel therapeutics; overexpression; pulmonary function; pulmonary vascular cells; pulmonary vascular remodeling; receptor; repaired; response; vascular abnormality

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的 肺纤维化（IPF）。诊断后的平均生存期仅约为3年，这与以下情况相似： 并不比与许多类型癌症相关的预后差。IPF的特征是上皮和 内皮细胞损伤，不同程度的炎症，异常肺血管重构，异常的 成纤维细胞增殖和细胞外基质沉积，导致肺结构扭曲， 器官功能障碍在IPF背景下，60-80%的患者发生肺动脉高压（PH）， 患者并预测疾病的死亡率。然而，驱动内皮损伤的机制， 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治疗在IPF患者中没有益处。因此，小说 可以被操纵以控制这些疾病中的血管重塑和PH的治疗靶点在 迫切需要科学突破 几丁质酶3-样1（CHI 3L 1）是原型几丁质酶样蛋白。循环CHI 3L 1水平的水平是 与对照组相比，IPF和其他形式的肺纤维化患者中的 与疾病严重程度相关。CHI 3L 1在肺中具有多种作用，在肺组织中起保护作用 通过改善上皮细胞死亡的损伤，以及通过其刺激替代（M2）的能力的促纤维化作用 巨噬细胞活化、成纤维细胞增殖和基质沉积。这些不同的反应是由 通过不同的细胞类型中的不同受体系统。然而，尽管其作为监管机构的重要性， 肺纤维化的损伤/修复反应，CHI 3L 1与血管的相互关系， 与肺纤维化相关的修复/重塑从未被研究过， CHI 3L 1通过什么途径介导血管细胞中的不同效应子应答还没有被表征。在 初步研究发现，肺动脉高压发生过程中， 纤维化在CHI 3L 1缺失小鼠中减轻，而在过表达CHI 3L 1的转基因小鼠中加重。我们 假设CHI 3L 1及其受体调节异常的肺血管重构， 肺纤维化中PH的发展。我们建议：1）定义CHI 3L 1的细胞效应及其在细胞中的作用。 2）确定CHI 3L 1及其受体在血管内皮细胞和平滑肌细胞上的作用; 在博来霉素肺结核小鼠模型中， 纤维化; 3）开发基于CHI 3L 1的治疗剂以治疗与纤维化相关的血管重塑和PH。 肺纤维化这些研究将确定CHI 3L 1信号在肺血管内皮细胞中的作用。 细胞，并可能揭示新的治疗选择，以减缓IPF中PH的发展。