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: 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
• 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

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.

肺纤维化会影响全球数百万的人。肺纤维化的一种常见形式是特发性 肺纤维化（IPF）。诊断后的平均生存率仅约3年，这与 并不比许多类型的癌症相关的预后差。 IPF的特征是上皮和 内皮细胞损伤，炎症程度不同，肺血管重塑异常，异常 成纤维细胞增殖和细胞外基质沉积，导致肺结构和 器官功能障碍。 IPF设置中肺动脉高压（pH）的发展发生在60-80％ 患者并预测疾病的死亡率。但是，造成内皮损伤的机制， 血管重塑异常，pH的发展知之甚少，目前可用 充当肺血管扩张剂的疗法对IPF患者没有有益。因此，新颖 可以操纵以控制血管重塑的治疗靶标和这些疾病中的pH 迫切需要科学突破。 几丁质酶3样1（CHI3L1）是原型几元酶样蛋白。循环CHI3L1水平的水平为 与对照组相比 与疾病的严重程度相关。 CHI3L1在肺中具有多种影响，在组织中起保护作用 通过改善上皮细胞死亡的损害，并通过其刺激替代性的能力（M2）来造成纤维化作用（M2） 巨噬细胞激活，成纤维细胞增殖和基质沉积。这些不同的响应是介导的 通过各种细胞类型的不同受体系统。但是，尽管它是作为监管者的重要性 肺纤维化的损伤/修复反应，CHI3L1和血管之间的相互关系 与肺纤维化相关的修复/重塑从未研究过，并且受体复合物 CHI3L1介导了血管细胞中不同效应子反应的尚未表征。在 初步研究，我们发现肺发育过程中肺高血压反应 在CHI3L1 NULL小鼠中减轻纤维化，并在过表达Chi3L1的转基因小鼠中加剧。我们 假设CHI3L1及其受体调节异常肺血管重塑和 肺纤维化中pH的发展。我们建议1）定义Chi3l1及其的细胞效应 血管内皮细胞和平滑肌细胞上的受体； 2）确定Chi3l1及其的作用 在肺部特征良好的博霉素小鼠模型中，血管重塑和pH的受体 纤维化； 3）开发基于CHI3L1的治疗剂，以治疗与之相关的血管重塑和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，并可能揭示新的治疗选择，以减慢IPF中pH的发展。