Sirtuins in Glaucomatous Optic Neuropathy

描述（由申请人提供）：该提案阐述了sirtuin-1 （Sirt1）的激活，一种可以调节基因表达的去乙酰化酶，将增加青光眼视网膜神经节细胞（RGC）的存活和视觉系统功能。Sirt1的激活对于热量限制诱导的年龄相关发病率的降低和寿命的延长至关重要。该酶主要通过组蛋白和其他蛋白质的去乙酰化作用，对代谢、线粒体功能和其他细胞功能产生影响。通过Sirt1激活，热量限制诱导的防止视网膜神经节细胞正常年龄相关损失的保护表明sirtuins与青光眼高度相关。越来越多的证据表明，通过摄入白藜芦醇（一种sirtuin活化剂和天然化合物，在红酒和花生等某些食物中含量丰富），可以获得许多（尽管不是全部）热量限制带来的有益益处。我们的总体假设是Sirt1激活的增加将保护青光眼小鼠模型的视网膜、视神经和大脑免受青光眼损伤。我们的一般方法是通过热量限制或膳食补充白藜芦醇来研究Sirt1激活增加的影响，并通过在rgc中缺乏Sirt1表达的转基因小鼠来确定Sirt1的作用。具体目的将是：1)确定Sirt1激活是否会减少视神经损伤后的RGC Thy-1基因表达缺失和RGC死亡；2)通过评估视网膜脂质过氧化、线粒体完整性和功能以及参与基因调控的关键蛋白（包括组蛋白和转录因子）的乙酰化，确定sirt1介导的RGC保护的生物学基础；3)确定Sirt1激活是否保留了中枢视觉系统通路的结构完整性和功能。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The present proposal evaluates the hypothesis that increased activation of sirtuin-1 protects against glaucomatous damage in the retina, optic nerve, and brain. The data generated will significantly enhance our basic understanding of sirtuin function in glaucoma, and assess whether targeting sirtuin-1 can lead to a novel glaucoma treatment.