Neuroprotective Role of Sirt6 in Glaucoma

项目名称：Sirt 6在青光眼中的神经保护作用 总结 青光眼是世界范围内第二大不可逆性致盲原因。它的特点是渐进的 视网膜神经节细胞（RGC）死亡和视神经变性。青光眼的主要危险因素包括 眼内压升高（IOP）、年龄和遗传背景。其中，只有IOP研究得很好， 作为青光眼唯一可治疗的靶点。然而，降低IOP并不总是阻止进展 青光眼目前迫切需要确定青光眼神经病变的其他机制，以进行治疗干预。 Sirtuin（Sirt）6是一种进化上保守的烟酰胺腺嘌呤二核苷酸 （NAD）依赖性组蛋白脱乙酰酶，并与酵母Sir 2蛋白共享同源物， 酵母的寿命。它是一种组蛋白H3赖氨酸9（H3 K9）和H3 K56脱乙酰酶，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 基因组不稳定性和维持葡萄糖稳态。Sirt 6的这些多重功能将其定位为 抗衰老分子Sirt 6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 整合了一系列新的方法，包括我们新开发的Sirt 6全局和条件敲除 /过表达小鼠，AAV 2介导的基因敲减，临床相关的非侵入性成像和功能 测试，最先进的成像来测试Sirt 6在预防糖尿病中起关键作用的假设。 青光眼中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 Sirt 6缺失导致视网膜和视神经类似青光眼的病理变化的假说; 2)检验增强Sirt 6表达防止视网膜和视神经病变的假设。 眼压升高诱发青光眼的神经。完成拟议的研究将提供重要的新的 这些知识可能会指导青光眼新疗法的开发。这一提议符合愿景 在NEI出版物中确定的研究优先事项，“视觉研究：需求，差距和机会”：1） 确定风险因素（如年龄和既往昏迷损伤）影响的机制 剩余的RGC轴突对升高的IOP的敏感性; 2）将分子生物学技术应用于RGC 神经科学剖析生存，轴突再生和生理学的重要因素; 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.