Sirtuins in Glaucomatous Optic Neuropathy

描述(由申请人提供)：这项建议针对的想法是，sirtuin-1(sirtuin-1)是一种可以调节基因表达的脱乙酰酶，它的激活将增加青光眼患者视网膜神经节细胞(RGC)的存活率和视觉系统功能。Sirt1的激活对于热量限制导致的与年龄相关的发病率的降低和寿命的延长至关重要。这种酶主要通过组蛋白和其他蛋白质的脱乙酰化来影响新陈代谢、线粒体功能和其他细胞功能。热量限制通过激活Sirt1对正常年龄相关的视网膜神经节细胞丢失的保护作用表明，sirtuins与青光眼高度相关。越来越多的证据表明，摄入白藜芦醇(一种sirtuin激活剂和天然化合物)可以产生许多(尽管不是全部)卡路里限制的有益益处，白藜芦醇在某些食物中富含，包括红酒和花生。我们的总体假设是，增加Sirt1的激活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害。我们的一般方法是研究通过限制热量或补充白藜芦醇来增加Sirt1活性的效果，并通过在其RGCs中使用缺乏SIRT1表达的转基因小鼠来确定Sirt1的作用。具体目标将是：1)确定Sirt1激活是否能减少视神经损伤后RGC Thy-1基因表达的丢失和RGC的死亡；2)通过评估视网膜脂质过氧化、线粒体的完整性和功能以及与基因调控有关的关键蛋白质(包括组蛋白和转录因子)的乙酰化来确定Sirt1介导的RGC保护的生物学基础；以及3)确定Sirt1激活是否保持了中枢视觉系统通路的结构完整性和功能。 公共卫生相关性：本提案评估了增加sirtuin-1的激活以保护视网膜、视神经和大脑免受青光眼损害的假说。产生的数据将大大增强我们对sirtuin在青光眼中功能的基本了解，并评估靶向sirtuin-1是否可以导致一种新的青光眼治疗方法。

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.