项目名称： 小鼠糖基化磷脂酰肌醇锚定高密度脂蛋白结合蛋白1（GPIHBP1）基因缺陷在糖尿病肾病中的作用及机制研究

项目编号： No.81470553

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 黄薇

作者单位： 北京大学

项目金额： 68万元

中文摘要： 糖尿病肾病（DN）是糖尿病最严重的血管并发症之一。GPIHBP1是新近发现的促进脂蛋白脂酶（LPL）降解甘油三酯（TG）的基因。预实验发现GPIHBP1基因敲除（-/-）的糖尿病小鼠出现明显高于对照组的白蛋白尿及肾小球肥大。为明确GPIHBP1基因在DN中的作用及机制，本项目将利用GPIHBP1-/-及其与LDL-R-/-杂交的双基因敲除小鼠，制备成DN模型，研究GPIHBP1基因缺陷对不同时期DN的影响。通过对血脂、肾游离脂肪酸组分的检测,肾形态及超微结构的影响，肾脂代谢、氧化、炎症、促纤维化及足细胞代谢相关基因蛋白的检测明确其机制。体外GPIHBP1-/-小鼠原代肾小球系膜细胞培养，在更深入研究作用机制的同时，可明确GPIHBP1基因对DN的影响是否一定程度依赖TG水平的改变。本研究将首次阐明GPIHBP1基因在DN中的作用及机制，为临床治疗DN提供新思路。

中文关键词： 糖基化磷脂酰肌醇锚定高密度脂蛋白结合蛋白1（GPIHBP1）；糖尿病微血管病变；糖尿病肾病；高甘油三酯血症；基因敲除小鼠

英文摘要： Diabetic nephropathy (DN) is one of the most serious vascular complications of diabetes. GPIHBP1 is a recently discovered gene that promotes the triglyceride (TG) degradation of Lipoprotein lipase (LPL). Our preliminary study showed significantly increases of urinary albumine and glomerular hypertrophy in GPIHBP1 knockout (-/-) diabetic mice compared with controls. To clarify the role of GPIHBP1 gene in different periods of DN, GPIHBP1-/ - and GPIHBP1-/- X LDL-R-/- double-knockout mice were used after induction of diabetes. The renal function, histology and ultrastructure were detected. To study the possible mechanisms, the compositions of plasma lipids and renal free fatty acids were studied. Measurements of relative genes and proteins levels of lipid metabolism, oxidation, inflammation, fibrosis and podocyte were also studied. The in vitro studies using primary cultured mesangial cells of GPIHBP1-/- mice were performed to further investigate the mechanisms. These in vitro studies could also identify if the effect of GPIHBP1 gene is dependent on TG levels. This is the first time to identify the role and mechanism of GPIHBP1 gene in the DN. It might be provide a new pathway in DN, and have an important significance. This study also counts for clinical therapy of DN.

英文关键词： GPIHBP1;diabetic-microangiopathy;diabetic nephropathy;hypertriglyceride;gene knock out mice