Neuroprotective Role of Sirt6 in Glaucoma

项目名称：SIRT6在青光眼中的神经保护作用 摘要 青光眼是全球第二大导致不可逆性失明的原因。它的特征是进步的 视网膜神经节细胞(RGC)死亡和视神经变性。青光眼的强烈危险因素包括 高眼压、年龄和遗传背景。其中，只有眼压研究得比较深入， 是治疗青光眼的唯一靶点。然而，降低眼压并不总是能阻止病情的发展 青光眼的症状。迫切需要确定青光眼中神经病变的其他机制，以便进行治疗干预。 Sirtuin(Sirt)6是进化上保守的烟酰胺腺嘌呤二核苷酸家族中的一员 (NAD)依赖组蛋白脱乙酰酶，并与酵母Sir2蛋白共享同源蛋白，关键调节 酵母的寿命。它是一种组蛋白H3赖氨酸9(H3K9)和H3K56去乙酰基酶，抑制转录 参与衰老和炎症的几种转录因子的活性，促进DNA修复，防止 基因组不稳定，维持葡萄糖动态平衡。SIRT6的这些多重功能使其成为一把钥匙 抗衰老分子。SIRT6在视网膜中表达，但其在青光眼中的作用尚不清楚。此应用程序将 集成了一系列新的方法，包括我们最新开发的SIRT6全局和条件基因敲除 /过表达小鼠，AAV2介导的基因敲除，临床相关的无创成像和功能 测试，最先进的成像测试，以验证SIRT6在预防糖尿病中发挥关键作用的假设 青光眼视网膜神经节细胞及其轴突的功能障碍/变性我们将：1)测试 假设SIRT6的缺失会导致类似青光眼的视网膜和视神经的病理变化； 2)测试增强SIRT6表达可防止视网膜和视神经病变的假设 神经在高眼压青光眼中的作用。拟议研究的完成将提供重要的新的 可能指导青光眼新疗法开发的知识。这项建议符合我们的设想。 NEI出版物《愿景研究：需求、差距和机遇》中确定的研究重点：1) 确定年龄和既往青光眼损伤等危险因素影响的机制 RGC剩余轴突对高眼压的易感性；2)将分子生物学技术应用于RGC 神经科学，剖析对生存、轴突再生和生理学重要的因素；3)探索 神经保护作为延长RGC功能和存活的方法。

Project title: Neuroprotective Role of Sirt6 in Glaucoma SUMMARY Glaucoma is the second leading cause of irreversible blindness worldwide. It is characterized as progressive retinal ganglion cell (RGC) death and optic nerve degeneration. Strong risk factors for glaucoma include elevated intraocular pressure (IOP), age and genetic background. Among them, only IOP is well-studied and serves as the only treatable target for glaucoma. However, lowering IOP does not always stop the progression of glaucoma. It is urgent to identify other mechanisms of neuropathy in glaucoma for therapeutic intervention. Sirtuin (Sirt) 6 is a member of the Sirts that are evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and share homolog with yeast Sir2 protein that critically regulates lifespan of yeast. It is a histone H3 lysine 9 (H3K9) and H3K56 deacetylase which represses the transcription activities of several transcription factors involved in aging and inflammation, promotes DNA repair, prevents genomic instability and maintains glucose homeostasis. These multiple functions of Sirt6 position it as a key anti-aging molecule. Sirt6 is expressed in the retina but its role in glaucoma is unknown. This application will integrate a series of novel approaches including our newly developed Sirt6 global and conditional knockout /overexpression mice, AAV2-mediated gene knockdown, clinic-relevant non-invasive imaging and functional tests, state-of-the-art imaging to test the hypothesis that Sirt6 plays a key role in the prevention of dysfunction/degeneration of retinal ganglion cells and their axons in glaucoma. We will: 1) test the hypothesis that loss of Sirt6 causes pathological changes in the retina and optic nerve resembling glaucoma; 2) test the hypothesis that boosting Sirt6 expression prevents pathological changes in the retina and optic nerve in IOP elevation-induced glaucoma. Completion of the proposed studies will provide important new knowledge that may guide the development of novel therapies for glaucoma. This proposal is in line with vision research priorities identified in the NEI Publication, “Vision Research: Needs, Gaps, & Opportunities”: 1) Determine the mechanisms by which risk factors, such as age and prior glaucomatous injury, influence susceptibility of remaining RGC axons to elevated IOP; 2) Apply molecular biology techniques to RGC neuroscience to dissect factors important for survival, axon regeneration, and physiology; 3) Explore neuroprotection as an approach for prolonging RGC function and survival.