Toll样受体2在湿性年龄相关性黄斑病变中的保护机制研究

Age-related macular degeneration is a progressive neurodegenerative disease that eventually leads to legal blindness. China has witnessed a great increase in AMD patients in recent years. Despite researchers have identified multiple pathogenic mechanisms in AMD; the treatment methods of this disease are limited. The pathological processes, including inflammation, oxidative damage, angiogenesis and so on, interact with each other and result in irreversible cellular damage and choroidal neovascularization (CNV) in and/or beneath retinal neurons. Our previous research has indicated the critical importance of toll-like receptor 2(TLR2), one of the pathogen-associated molecular patterns, functioning in human fetal retinal pigment epithelial cells, and influencing the formation and development of CNV in human AMD samples. The aim of this research is to: 1.establish a model of human choroidal micro-vascular endothelial cells (HCMECs) activation and observe the function of TLR2-activated/inhibited HCMECs, observing the inflammatory, chemotactic and angiogenesis genes or proteins expression via RT-PCR and Western blot; observing apoptosis via TUNEL. 2.investigate the function of activation/inhibition of TLR2 pathway in the spontaneous CNV mouse model JR mice via FFA, immunohistochemistry and immunofluorescence. Our finding will cast new lights on the functional role and potentially therapeutic effects of TLR2 in wet age-related macular degeneration.

AMD是严重的致盲性眼病,我国AMD患者呈大幅增多之势。尽管对其发病机制有了一定理解,但其治疗手段却极其有限。申请人前期研究中发现Toll样受体2在原代培养的人RPE细胞中发挥关键作用,并在人眼CNV标本中进行了验证,证明TLR2能通过RPE影响CNV，但TLR2对CNV的完整致病和保护机制还不清楚。本项目拟在通过系统性干预TLR2及其通路,对脉络膜微血管内皮细胞在AMD中的致病作用进行研究。1.建立人脉络膜微血管内皮细胞活化模型,通过干预TLR2及其通路,检测其在炎症、趋化及血管生成相关方面的作用;及其在诱导细胞活化与凋亡方面的相关机制。2.利用自发型CNV模型JR小鼠，系统性给予TLR2中和抗体、拮抗剂和抑制剂,通过形态学和分子生物学方法研究CNV变化并探讨其相关机制。通过上述研究,以期进一步阐明TLR2在湿性AMD的作用机制,为寻找AMD新的治疗方案提供理论依据。

年龄相关性黄斑病变（AMD）是严重的致盲性眼病,我国AMD患者呈大幅增多之势。尽管对其发病机制有了一定理解, 但其治疗手段却极其有限。前期研究中发现Toll样受体2在原代培养的人RPE细胞中发挥关键作用,并在人眼CNV标本中进行了验证,证明TLR2能通过RPE影响CNV，但TLR2对CNV的完整致病和保护机制还不清楚。本项目通过系统性干预TLR2及其通路,对脉络膜微血管内皮细胞在AMD中的致病作用进行研究。1.建立人脉络膜微血管内皮细胞活化模型,通过干预TLR2及其通路,检测其在炎症、趋化及血管生成相关方面的作用;及其在诱导细胞活化与凋亡方面的相关机 制。2.利用自发型CNV模型JR小鼠，系统性给予TLR2中和抗体、拮抗剂和抑制剂,通过形态学和分子生物学方法研究CNV变化并探讨其相关机制。通过上述研究,进一步阐明了TLR2在湿性AMD的作用机制,为寻找AMD新的治疗方案提供理论依据。截至目前，本项目已发表SCI论文3篇，拟发表SCI论文2-3篇。