Sirtuins in Glaucomatous Optic Neuropathy

摘要 这项建议解决了sirtuin-1(sirtuin-1)的激活这一想法，sirtuin-1(Sirt1)是一种可以调节 基因表达，将增加视网膜神经节细胞(RGC)的存活和视觉系统功能 青光眼。Sirt1的激活对于热量限制诱导的年龄相关的减少是必不可少的 发病率和寿命的增加。这种酶作用于新陈代谢、线粒体 而其他细胞的功能主要是通过组蛋白和其他蛋白质的脱乙酰化实现的。卡路里 Sirt1对正常年龄相关性视网膜神经节细胞损伤的保护作用 激活表明sirtuins与青光眼高度相关。越来越多的证据表明 虽然不是全部，但限制卡路里的许多有益的好处可以通过喂食来诱导 白藜芦醇是一种sirtuin激活剂和天然化合物，富含在某些食物中，包括 红酒和花生。我们的总体假设是，增加Sirt1的激活将防止 青光眼小鼠模型视网膜、视神经和脑的青光眼损害。我们的 一般的方法将是研究通过限制热量增加Sirt1激活的效果 或通过饮食补充白藜芦醇，并通过使用转基因来确定Sirt1的作用 视网膜节细胞中SIRT1表达缺失的小鼠。具体目标将是：1)确定Sirt1是否 激活可减少视神经损伤后RGC Thy-1基因表达缺失和RGC死亡 2)通过评估视网膜功能来确定Sirt1介导的RGC保护的生物学基础 脂质过氧化、线粒体的完整性和功能以及蛋白质的乙酰化(包括 组蛋白和转录因子)关键参与基因调控；以及3)确定 SIRT1的激活保护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.