VEGFR1介导巨噬细胞功能转变对年龄相关性黄斑变性脉络膜新生血管形成的调控机制

As the most quickly increased blinding ocular fundus disease among the elderly in China，age-related macular degeneration (AMD) is hard to be treated and choroid neovascularization (CNV) is the primary pathological characteristic of wet AMD. VEGFR1 is one of the important molecules affecting the formation of CNV, however, it is not clear about its regulatory mechanism in the process of choroid neovascularization. Recent studies have shown that macrophages polarization is closely related with the incidence of CNV, revealing that the ratio of M1/M2 regulates the formation of CNV. Our preliminary experiments reveal that 1) macrophages VEGFR1 knockout inhibited choroid neovascularization, and 2) VEGFR1 knockout promoted M1 cells related markers’ expression. Therefore, we propose a hypothesis: VEGFR1 inhibits the M1 macrophages polarization and reduces M1/M2 ratio, so that it promotes CNV formation by changing macrophage dynamic function. This study intends to use the macrophages specific VEGFR1 gene knockout mice to establish a model of laser induced CNV, adopting a variety of cell culture and molecular biology methods, to explore the effect of macrophages the VEGFR1 signal on choroid neovascularization and mechanism of VEGFR1 regulating macrophage activation and polarization in choroid neovascularization. This study will provide a theoretical foundation to understand the pathogenesis and find new treatments of choroid neovascular diseases in AMD.

年龄相关性黄斑变性（AMD）是我国老年人中发病率急剧升高的一种致盲眼病，治疗棘手，脉络膜新生血管(CNV)是湿性AMD的基本病理特征。VEGFR1作为影响CNV的重要信号，但其调控机制尚不明确。新近研究表明巨噬细胞极化与CNV关系密切，认为M1/M2的比例调控CNV发生。预实验发现：1）巨噬细胞VEGFR1基因敲除抑制了CNV形成，2）VEGFR1基因敲除促进M1型细胞标志的表达；因此，我们提出假说：VEGFR1抑制了巨噬细胞M1型极化，使M1/M2相对降低，通过介导细胞动态功能变化促进CNV形成。本项目拟采用巨噬细胞特异性VEGFR1基因敲除小鼠建立激光诱导CNV模型；运用多种细胞培养和分子生物学方法，研究VEGFR1信号对巨噬细胞极化的调节及其对CNV的作用；探讨VEGFR1对年龄相关性黄斑变性CNV形成的体内外调控机制；为AMD脉络膜新生血管的发病机制研究和治疗提供理论基础。

年龄相关性黄斑变性（AMD）是我国老年人中发病率急剧升高的一种致盲性眼病，治疗棘手，脉络膜新生血管(CNV)是湿性AMD的基本病理特征。VEGFR1作为影响CNV的重要信号，但其调控机制尚不明确。研究表明M1型巨噬细胞极化与CNV关系密切，然而巨噬细胞VEGFR1是否影响CNV的发生尚不清楚。本研究拟运用巨噬细胞VEGFR1敲除小鼠建立CNV模型，探讨VEGFR1在脉络膜新生血管形成中对巨噬细胞M1型激活及极性转化的影响及机制。研究发现靶向VEGFR1促进了巨噬细胞M1型极化过程，使M1相关标志的水平和细胞数目升高，抑制了内皮细胞的迁移，从而可能在一定程度上抑制了CNV形成。此项研究明确了巨噬细胞VEGFR1对脉络膜新生血管形成的作用，阐明了VEGFR1调控M1型巨噬细胞极化及其相关的机制，为AMD等脉络膜新生血管性疾病的发病机制研究和治疗靶点提供理论基础。