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Sirtuins in Glaucomatous Optic Neuropathy

Sirtuins 在青光眼视神经病变中的作用

基本信息

批准号：
8041809
负责人：
ROBERT N WEINREB
金额：
$ 59.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8041809
关键词：
Acute Address Adult Affect Automobile Driving Axon Biological Biological Preservation Blueberries Brain Caloric Restriction Cell Death Cell Survival Cell physiology Code Cytoprotection Data Deacetylase Dendrites Dietary Supplementation Disease Progression Electroretinography Elements Enzymes Experimental Models Family member Food Gene Expression Gene Expression Regulation Glaucoma Histone Deacetylation Histones Knockout Mice Lateral Geniculate Body Lead Link Lipid Peroxidation Longevity Mammals Measures Mediating Messenger RNA Metabolism Mitochondria Modeling Molecular Morbidity - disease rate Neurodegenerative Disorders Neurons Optic Nerve Optic Nerve Injuries Pathway interactions Pattern Peanuts - dietary Performance Physiologic Intraocular Pressure Protein Acetylation Proteins Resveratrol Retina Retinal Retinal Ganglion Cells Role Sirtuins Specificity Structure Supplementation Synapses Transgenic Mice Visual Cortex Visual system structure Wild Type Mouse age related base cell injury cell type feeding in vivo mouse model neuroprotection normal aging novel optic nerve disorder protective effect red wine research study response retinal neuron transcription factor

项目摘要

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.

描述（由申请人提供）：该提案提出了这样的想法，即激活sirtuin-1（Sirt 1），一种可以调节基因表达的脱乙酰酶，将增加青光眼中视网膜神经节细胞（RGC）的存活和视觉系统功能。Sirt 1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增加是必不可少的。这种酶主要通过组蛋白和其他蛋白质的脱乙酰化作用对代谢、线粒体功能和其他细胞功能发挥作用。通过Sirt 1激活，热量限制诱导的对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，虽然不是全部，但许多热量限制的有益效果可以通过喂食白藜芦醇来诱导，白藜芦醇是一种抗衰老酶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激活将防止青光眼小鼠模型的视网膜、视神经和大脑中的青光眼损伤。我们的一般方法将是调查增加Sirt 1激活的热量限制或饮食白藜芦醇补充剂的影响，并确定Sirt 1的作用，通过使用转基因小鼠缺乏SIRT 1表达在他们的RGCs。具体目标是：1）确定Sirt 1激活是否将减少视神经损伤后RGC的Thy-1基因表达损失和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蛋白质的乙酰化来确定Sirt 1介导的RGC保护的生物学基础（包括组蛋白和转录因子）关键参与基因调控;以及3）确定Sirt 1激活是否保持了中枢视觉系统通路的结构完整性和功能。公共卫生关系：目前的建议评估的假设，增加激活sirtuin-1保护视网膜，视神经和大脑中的神经性损伤。所产生的数据将显著增强我们对sirtuin在青光眼中的功能的基本理解，并评估靶向sirtuin-1是否可以导致新的青光眼治疗。