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

肺纤维化影响着全世界数以百万计的人。肺纤维化的一种常见形式是特发性。 肺纤维化(IPF)。确诊后的平均生存期只有大约3年，这与如果 与许多类型的癌症相关的预后并不差。IPF的特点是上皮性和 内皮细胞损伤，不同程度炎症，肺血管重构异常，异常 成纤维细胞增殖和细胞外基质沉积，导致肺结构扭曲和 器官功能障碍。发生在IPF环境中的肺动脉高压(PH)发生在60%-80% 并预测这种疾病的死亡率。然而，驱动内皮损伤的机制， 血管重构异常和肺高压的发生发展目前尚不清楚。 作为肺血管扩张剂的治疗对IPF患者没有好处。因此，小说 在这些疾病中，可以控制血管重塑和PH的治疗靶点是 迫切需要科学突破。 几丁质酶3样蛋白1(CHI3L1)是几丁质酶样蛋白的原型。循环CHI3L1水平如下 与对照组相比，IPF和其他形式的肺纤维化患者的水平更高，而且他们 与疾病的严重程度相关。CHI3L1在肺中有多种作用，在组织中起保护作用 通过改善上皮细胞死亡造成的损伤，以及通过刺激替代(M2)的能力发挥促纤维化作用(M2) 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 通过不同细胞类型中不同的受体系统。然而，尽管它作为监管机构的重要性 肺纤维化的损伤/修复反应及CHI3L1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，而且受体复合体 CHI3L1通过什么在血管细胞中介导不同的效应反应尚未确定。在……里面 初步研究发现，在肺高压的发展过程中，我们的反应是 CHI3L1基因缺失的小鼠肝纤维化减轻，过度表达CHI3L1的转基因小鼠肝纤维化加重。我们 假设CHI3L1及其受体调节异常的肺血管重塑 肺纤维化中肺高压的发生发展。我们建议1)定义CHI3L1的细胞效应及其 血管内皮细胞和平滑肌细胞上的受体；2)确定CHI3L1及其受体的作用 博莱霉素性肺损伤小鼠模型中血管重塑和PH的受体 3)开发以CHI3L1为基础的治疗药物，以治疗与以下相关的血管重构和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，以减缓肺间质纤维化的发展。

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.