AIBP-mediated neuroprotection in glaucomatous optic neuropathy

青光眼是世界范围内导致失明的主要原因，而胶质细胞驱动的神经炎症是导致青光眼的关键因素 青光眼的发病机制。越来越多的临床研究证据表明，原发性开角型青光眼 与Toll样受体4(TLR4)、线粒体细胞色素C氧化酶的单核苷酸多态性有关 氧化磷酸化(OXPHOS)复合体-IV的亚基I，三磷酸腺苷结合盒转运体A1和 胆固醇-24S-羟基酶，提示TLR4介导的神经炎症、胆固醇外流和/或 OXPHOS应激介导的线粒体功能障碍在青光眼发病机制中起重要作用。载脂蛋白A-I结合 蛋白(AIBP)是一种分泌型蛋白，由APOA1BP基因编码，是一种选择性调节蛋白。 细胞胆固醇代谢，通过与TLR4结合靶向炎症细胞。胆固醇消耗来自 炎症细胞减少了脂筏的丰度和受体(如TLR4)的膜占有率 调节炎症信号。来自我们小组的新证据表明，AIBP缺乏与 青光眼中胶质细胞驱动的炎症性TLR4/IL-1β信号轴和线粒体功能障碍 退化。除了保护视网膜神经节细胞(RGC)免受神经炎症，AIBP还防止 青光眼神经变性的RGC线粒体功能障碍。在初步研究中，我们证明了 AIBP在青光眼患者和小鼠视网膜神经节细胞及其轴突中的表达显著降低。 Müller胶质细胞，腺相关病毒载体扩增视网膜AIBP表达对RGC的保护作用 并在体内保存实验性青光眼的视觉功能。此外，应用重组AIBP治疗 在体外，蛋白质促进Müler神经胶质细胞的线粒体功能，以对抗压力升高。基于我们之前的 而这些发现，我们建议测试AIBP控制视网膜神经炎症和 RGC线粒体功能障碍，导致青光眼神经变性，以及测试 提高AIBP在视网膜中表达的治疗潜力。这项建议的具体目的是：(1)界定 AIBP控制炎性Müler神经胶质细胞TLR4-脂筏活化的机制；(2) 确定AIBP扩增对大鼠线粒体网络和生物能量学的保护机制 青光眼视网膜节细胞和Müler胶质细胞；以及(3)确定AIBP的治疗作用。 表达影响结构的完整性和连接视网膜节细胞和中央视觉通路的突触。我们的建议 研究将探索可能将神经炎症调节与眼压升高联系起来的新途径 线粒体功能和细胞胆固醇代谢。这项工作还可能导致开发一种新的 青光眼治疗。

Glaucoma is a leading cause of blindness worldwide and glia-driven neuroinflammation is a key element in the pathogenesis of glaucoma. Increasing evidence from clinical studies indicate that primary open-angle glaucoma is linked to single-nucleotide polymorphisms of toll-like receptor 4 (TLR4), mitochondrial cytochrome c oxidase subunit I of the oxidative phosphorylation (OXPHOS) complex-IV, ATP-binding cassette transporter A1 and Cholesterol-24S-hydroxylase, suggesting that TLR4-mediated neuroinflammation, cholesterol efflux and/or OXPHOS stress-mediated mitochondrial dysfunction play roles in glaucoma pathogenesis. ApoA-I binding protein (AIBP), encoded by the APOA1BP gene, is a secreted protein, which serves as a selective regulator of cellular cholesterol metabolism, targeting inflammatory cells via its binding to TLR4. Cholesterol depletion from inflammatory cells reduces lipid raft abundance and the membrane occupancy of receptors (such as TLR4) that mediate inflammatory signaling. Emerging evidence from our group showed that AIBP deficiency is associated with glia-driven inflammatory TLR4/interleukin-1β signaling axis and mitochondrial dysfunction in glaucomatous degeneration. In addition to protecting retinal ganglion cells (RGCs) against neuroinflammation, AIBP prevents RGC mitochondrial dysfunction in glaucomatous neurodegeneration. In preliminary studies, we demonstrated that AIBP expression is highly reduced in glaucomatous human and mouse RGCs and their axons, as well as Müller glia, and that amplification of retinal AIBP expression by adeno-associated virus delivery protects RGCs and preserves visual function in experimental glaucoma in vivo. In addition, treatment with recombinant AIBP protein promotes mitochondrial function in Müller glia against elevated pressure in vitro. Based on our previous and these findings, we propose to test the novel concept that AIBP controls retinal neuroinflammation and the RGC mitochondrial dysfunction, which lead to glaucomatous neurodegeneration, as well as to test the therapeutic potential of raising AIBP expression in the retina. The Specific Aims of this proposal are: (1) to define the mechanisms by which AIBP controls TLR4-lipid raft activation in inflammatory Müller glial cells; (2) to determine the protective mechanisms of AIBP amplification on mitochondrial network and bioenergetics in glaucomatous RGCs and Müller glial cells; and (3) to determine how therapeutic augmentation of AIBP expression impacts structural integrity and synapses linking RGCs and the central visual pathway. Our proposed studies will explore novel pathways which potentially link neuroinflammation regulation to elevated IOP-mediated mitochondrial function and cellular cholesterol metabolism. This work may also lead to the development of a new glaucoma therapy.