Signal transduction mechanisms of neuroprotective substances in animal models of glaucoma and the role of the protein high-mobility group box-1 (HMGB-1)

神经保护是青光眼治疗中的一个挑战，是作为降低眼压手术的辅助治疗。不同的物质已被证明具有神经保护作用，如神经营养因子、造血因子GM-CSF、抗vegf和applha2 -肾上腺素能激动剂溴胺酮。然而，这些物质在视网膜中的信号转导机制尚不清楚。本提案的第一个目标是仔细检查青光眼模型中视网膜内与神经保护活动相关的细胞信号。第二个目标是揭示神经保护是否涉及在急性和慢性视网膜变性中发现的核蛋白高迁移性群盒-1 （HMGB-1）。初步研究显示，暴露于眼压升高诱导的神经节细胞死亡的视网膜中，HMGB-1表达强烈。我们在可调节和维持的高压条件下建立了体内青光眼模型和体外器官型培养模型，结果表明进行性神经节细胞存活/死亡与HMGB-1调控有关。我们建议使用神经保护药物（如GM-CSF、溴胺酮、抗vegf）监测神经元存活，旨在提供HMGB-1在何处以及如何干扰细胞信号级联反应的信息，这些信号级联反应最终导致青光眼的有益结果。

Neuroprotection is a challenge in glaucoma therapy and is offered as subsidiary treatment to IOP-lowering procedures. Different substances have been shown to be neuroprotective such as neurotrophins, the hemopoietic factor GM-CSF, anti-VEGF and the aplha2-adrenergic agonist brimonidin. However, the signal transduction mechanisms of these substances remain unknown in the retina. The first goal of this proposal is to scrutinise cell signalling associated with neuroprotective activity within the retina in glaucoma models. The second goal is to unravel whether neuroprotection involves the nuclear protein high-mobility group-box-1 (HMGB-1) discovered in acutely and chronically degenerating retina. The initial studies revealed a strong expression of HMGB-1 in the retina exposed to IOP-elevation-induced ganglion cell death. We generated both in vivo glaucoma models and in vitro organotypic culture models under adjustable and maintained high pressure and showed that progressive ganglion cell survival/death is associated with HMGB-1 regulation. We propose that neuron survival will be monitored using neuroprotective drugs (e.g. GM-CSF, brimonidin, anti-VEGF) aiming to provide information, where and how HMGB-1 interferes with the cell signalling cascades which culminate to beneficial outcomes in glaucoma.