LPA及其受体在调控腰椎黄韧带增生纤维化中的作用及机制研究

项目名称： LPA及其受体在调控腰椎黄韧带增生纤维化中的作用及机制研究

项目编号： No.81501905

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张凯

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 黄韧带的增生肥厚是腰椎退变性管狭窄症主要的病理变化之一。国内外学者研究显示黄韧带增生肥厚可能与多种损伤引起的慢性炎症相关的损伤修复过程有关，本课题组前期研究发现溶血磷脂酸（LPA）及其受体在黄韧带的增生纤维化过程中起了重要的作用，但其详细机制不明确。为进一步探讨LPA及其受体在腰椎黄韧带增生纤维化中的调控作用，本课题组拟首先通过对腰椎黄韧带组织样本LPA受体表达谱的研究，筛选与腰椎黄韧带增生纤维化相关特异性受体亚型；其次观察外源性LPA作用后体外培养的黄韧带细胞增殖、迁移、凋亡等情况以及生物因子TGF-β1、CTGF、MMP-2,9等的表达变化，分析参与此过程的可能信号通路；最后通过体内外实验观察LPA受体拮抗剂或基因沉默对黄韧带增生纤维化的影响。通过本课题试图阐明LPA调控黄韧带纤维化的作用机制，为黄韧带退变相关疾病的药物、生物治疗提供新思路和新途径。

中文关键词： 黄韧带；纤维化；溶血磷脂酸；腰椎

英文摘要： The pathomechanism underlying central lumbar spinal stenosis is predominantly related to hypertrophied ligamentum flavum （LF）and accumulation of inflammation-related scar tissue contribute to LF hypertrophy and fibrosis. Our previous study showed that hypertrophy and fibrosis of LF in lumbar spinal stenosis is associated with increased expression of Lysophosphatidic acid (LPA) and LPA receptors (LPARs), however, the regulation mechanisms have not yet been elucidated. The current project attempts to elucidate the mechanism how LPA and LPARs can regulate the pathogenesis of LF fibrosis. Firstly, the expression of LPAR subtypes will be detected by molecular biological methods in the LF from patients. Secondly, the possible cellular and molecular mechanisms of LPA-LPARs action will be investigated through the use of in vitro and in vivo experiments. Finally, anti-fibrotic therapies by down-regulation or blockade of LPA receptors will also be investigated in vitro and in vivo. The results of this project will help to better understand the pathogenesis of LF fibrosis and may provide a potential biological method for lumbar spinal stenosis.

英文关键词： ligamentum flavum;fibrosis;lysophosphatidic acid;lumbar