Rhamnazin调控角膜炎症及其VEGFR2-NF-κB与JAK/STAT3通道依赖机制研究

The corneal inflammation is the main blinding cause of corneal disease,the incidence of which is secondary to the cataract. In our previous study, VEGFR2 has been found to be exclusively expressed in the inflammatory cornea. Rhamnazin, the potent VEGFR2 inhibitor, could inhibit tumor angiogenesis and suppress inflammation by inhibition of VEGFR2 phosphorylation and its downstream signaling pathways. VEGFR2 has been recently been detected to induce inflammation through JAK/STAT3 and FAK/IKK/NF-ҡB signaling pathways in other tissues. Therefore, we hypothesize that whether Rhamnazin could suppress corneal inflammation through inactivating VEGFR2-JAK/STAT3 and VEGFR2-FAK/IKK/NF-ҡB signaling pathways. To prove that, We will firstly evaluated the expression of VEGFR2 in normal corneal tissues and those with inflammation. The lentivirus expression vector VEGFR2 and VEGFR2-shRNA will be constructed to modulate VEGFR2 expression in vitro and in vivo. And then we will construct lentivirus expression vector VEGFR2 and VEGFR2-shRNA to modulate VEGFR2 expression in vitro and in vivo, and examine the roles of VEGFR2-JAK/STAT3 and VEGFR2-FAK/IKK/NF-ҡB signaling pathways. Finally, We will examine the role of Rhamnazin in corneal inflammation induced by VEGR2 mediated JAK/STAT3、FAK/IKK/NF-ҡB singaling pathway in cell and animal corneal inflammationmodel. We expect to reveal the role and mechanism of VEGFR2-mediated corneal inflammation, and develop a new anti-inflammatory therapeutic compound.

角膜病是最常见的致盲性眼病之一, 炎症及新生血管是导致角膜盲的主要原因。我们前期发现VEGFR2表达于人类炎症角膜，Rhamnazin能通过抑制VEGFR2磷酸化及其下游信号通道，抑制肿瘤血管新生、减轻炎症。研究证明VEGFR2可以通过激活JAK/STAT3、FAK/IKK/NF-ҡB信号转导通路参与炎症和新生血管的形成。因此，我们推测Rhamnazin可能依赖VEGFR2-JAK/STAT3、VEGFR2-FAK/IKK/NF-ҡB信号转导通路来调控角膜炎症。我们拟通过制造体内外角膜炎性模型、观察和分析沉默和过表达VEGFR2，探讨VEGFR2对角膜炎症细胞的作用；并阐明Rhamnazin对VEGFR2-JAK/STAT3、VEGFR2-FAK/IKK/NF-ҡB信号通路的影响。该研究为角膜炎症发生的分子机制提供新的研究思路，为设计合理的抗炎药物及寻找有效的抗炎靶点提供了理论基础。

角膜病是最常见的致盲性眼病之一, 炎症及新生血管是导致角膜盲的主要原因，研究角膜病的治疗方法有极大的社会和经济效应。本课题组前期发现VEGFR2表达于人类炎症角膜，Rhamnazin能通过抑制VEGFR2磷酸化及其下游信号通道，抑制肿瘤血管新生、减轻炎症。研究证明VEGFR2可以通过激活JAK/STAT3、FAK/IKK/NF-B信号转导通路参与炎症和新生血管的形成。在过去的4年里，本课题组采用STAT3特异性抑制剂、IKK特异性抑制剂、Rhamnazin（主要是JNK/ SAPK 和p38 MAKP 信号转导通路）作用于角膜细胞炎症模型（巨噬细胞RAW264.7致炎的人角膜上皮细胞）和动物模型（角膜碱烧伤和角膜接触镜模型）进一步证明Rhamnazin是否通过抑制VEGFR2与影响角膜炎症细胞内JAK/STAT3、FAK/IKK/NF-ҡB信号传导通道而发挥作用，进而研究角膜细胞在炎症刺激下，Rhamnazin是如何起作用。外源性给予 VEGFR2激动剂及其抑制剂是否会影响角膜炎症细胞生物学功能与其最佳浓度和作用时间，炎症细胞内VEGFR2过表达或沉默对角膜炎症的发生有何影响。更为深远的意义是能帮助我们寻找到有效的抑制角膜炎症发展的药物，并摸索其最佳浓度，为角膜炎患者治疗提供高价值数据资料。这项研究能取得的社会价值及市场效益无可估量。本课题的顺利实施将能解决目前眼科相关领域遇到的一系列难题， 能在全球角膜炎患者中快速应用与推广，具有很大的市场潜力和举足轻重的经济地位，能进一步推动我国医学事业向高新尖技术发展，具有重大的医学价值和社会价值。

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