Sirtuins in Glaucomatous Optic Neuropathy

摘要 这项提议提出了这样的想法，即激活sirtuin-1（Sirt 1），一种脱乙酰酶，可以调节 基因表达，将增加视网膜神经节细胞（RGC）的生存和视觉系统功能， 青光眼Sirt 1的激活对热量限制诱导的年龄相关性降低至关重要。 发病率和寿命延长。这种酶对新陈代谢、线粒体 功能，以及其他细胞功能主要通过组蛋白和其他蛋白质的脱乙酰化来实现。热量 Sirt 1对视网膜神经节细胞正常年龄相关损失的限制性保护作用 激活表明sirtuins与青光眼高度相关。越来越多的证据表明 尽管不是全部，但许多热量限制的有益效果可以通过喂食来诱导 白藜芦醇，一种sirtuin激活剂和天然化合物，富含某些食物，包括 红酒和花生我们的总体假设是，增加Sirt 1激活将保护 青光眼小鼠模型的视网膜、视神经和脑的青光眼性损害。我们 一般的方法将是研究通过热量限制增加Sirt 1激活的效果 或通过膳食白藜芦醇补充剂，并通过使用转基因技术鉴定Sirt 1的作用。 在RGCs中缺乏SIRT 1表达的小鼠。具体目标是：1）确定Sirt 1是否 激活将减少RGC的Thy-1基因表达损失和视神经损伤后RGC的死亡。 2）通过评估视网膜损伤，确定Sirt 1介导的RGC保护的生物学基础。 脂质过氧化、线粒体完整性和功能以及蛋白质（包括 组蛋白和转录因子）关键参与基因调控;和3）以确定是否 Sirt 1的激活保留了中枢视觉系统通路的结构完整性和功能。

ABSTRACT This proposal addresses the idea that activation of sirtuin-1 (Sirt1), a deacetylase that can regulate gene expression, will increase retinal ganglion cell (RGC) survival and visual system function in glaucoma. Activation of Sirt1 is essential to caloric restriction-induced reduction of age-related morbidity and increase of lifespan. This enzyme exerts its effects on metabolism, mitochondrial function, and other cell functions largely by deacetylation of histones and other proteins. Caloric restriction-induced protection against the normal age-related loss of retinal ganglion cells by Sirt1 activation suggests that the sirtuins are highly relevant to glaucoma. Growing evidence indicates that many, though not all, of the salutary benefits of caloric restriction can be induced by feeding with resveratrol, a sirtuin activator and natural compound, that is enriched in certain foods including red wine and peanuts. Our overall hypothesis is that increased Sirt1 activation will protect against glaucomatous damage in the retina, optic nerve, and brain of mouse models of glaucoma. Our general approach will be to investigate the effect of increasing Sirt1 activation by caloric restriction or by dietary resveratrol supplementation and to identify the role of Sirt1 by the use of transgenic mice lacking SIRT1 expression in their RGCs. Specific Aims will be: 1) to determine whether Sirt1 activation will reduce RGC loss of Thy-1 gene expression and RGC death following optic nerve injury; 2) to determine the biological basis of Sirt1-mediated RGC protection by evaluating retinal lipid peroxidation, mitochondrial integrity and function, and acetylation of proteins (including histones and transcription factors) critically involved in gene regulation; and 3) to determine whether Sirt1 activation preserves the structural integrity and function of the central visual system pathway.