巨噬细胞极化及定向调控对年龄相关性黄斑变性影响的研究

Wet age-related macular degeneration (wAMD) is the global leading cause of blindness in people over 50 years of age. The prevalence of wAMD is highest in China, with age- and gender-adjusted odds ratio 4.30, if compared with Caucasians. wAMD is now becoming a major public health problem that has a devastating effect upon patients, families and marked adverse financial consequences. Current treatment paradigms are directed at anti-vascular endothelial growth factor (VEGF) for Choroidal neovascularization (CNV), but do not address the underlying disease pathology, thus lots of patients responded poorly to the treatment. Our preliminary study showed that polarization of macrophages played an important role in different stages of wAMD, which is probably one of the causes of inflammatory infiltration and fibrosis. Based upon our precious studies, in this project, to determine the role of macrophages in wAMD, we attempt to investigate the dynamic spatiotemporal expression of macrophages (including M1 and M2) in the laser-induced CNV model.

湿性年龄相关性黄斑变性（wAMD）是引起全球老年人盲目的最主要原因。我国汉族人群易感，发病率最高，是白人的4.3倍，给家庭及社会带来沉重负担，已成为重大公共卫生问题。目前临床上采用抗VEGF治疗，未触及病机本质，故部分患者疗效欠佳，视功能难恢复。我们前期研究显示巨噬细胞极化参与了不同阶段疾病发展。本课题拟在前期工作基础上，通过观察激光诱导脉络膜新生血管（CNV）模型中巨噬细胞（M、M1和M2）的动态时空表达，探讨其在CNV发展转归中的作用。

巨噬细胞作为先天性免疫系统中的重要成员之一，在AMD的发生发展中起着重要作用，其极化的不同亚型在AMD新生血管形成及其瘢痕化中起到调节作用。本研究通过体外和体内实验观察了巨噬细胞极化现象在脉络膜新生血管形成中的时空表达。结果发现：（1）激光诱导小鼠CNV模型在观察巨噬细胞极化现象时是可行的，新生血管面积在14天时最大，之后逐渐减小；（2）分别使用RBPJ、CD68和MAF、CD163可以从组织学上鉴定出巨噬细胞不同极化亚型M1型和M2型；（3）巨噬细胞极化随着小鼠脉络膜新生血管的形成发生不同亚型的转变，从M1型为主变为M2型为主；（4）在湿性AMD患者房水中检测到趋化因子的水平，M1/M2型巨噬细胞相关的因子HCC-1(CCL14)在疾病组明显关于对照组（P<0.05），提示巨噬细胞极化可能参与了AMD的病理过程。