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）：该提案解决了以下想法：sirtuin-1（SIRT1）的激活（SIRTUIN-1）是一种可以调节基因表达的脱乙酰基酶，将增加视网膜神经节细胞（RGC）的生存和视觉系统在青光眼中的功能。 SIRT1的激活对于限制年龄相关的发病率和寿命增加至关重要。这种酶对新陈代谢，线粒体功能以及其他细胞功能的影响很大程度上通过组蛋白和其他蛋白质的脱乙酰化。通过SIRT1激活对正常年龄相关的视网膜神经节细胞损失的热量限制诱导的保护表明，Sirtuins与青光眼高度相关。越来越多的证据表明，许多（尽管不是全部）热量限制的有益益处可以通过用白藜芦醇（一种sirtuin激活剂和天然化合物）喂养，这些剂量富含某些食物，包括红葡萄酒和花生。我们的总体假设是，增加的SIRT1激活将预防青光眼小鼠模型的视网膜，视神经和大脑中的青光眼损伤。我们的一般方法是研究通过热量限制或补充饮食白藜芦醇增加SIRT1激活的效果，并通过使用在RGC中缺乏SIRT1表达的转基因小鼠来鉴定SIRT1的作用。具体目标是：1）确定SIRT1激活是否会减少视神经损伤后THY-1基因表达和RGC死亡的RGC丧失； 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（包括组蛋白和转录因子），确定SIRT1介导的RGC保护的生物学基础； 3）确定SIRT1激活是否保留了中央视觉系统途径的结构完整性和功能。公共卫生相关性：本提案评估了以下假设：SIRTUIN-1的激活增加可预防视网膜，视神经和大脑中的青光眼损害。产生的数据将显着增强我们对青光眼中SIRTUIN功能的基本了解，并评估靶向Sirtuin-1是否会导致新的青光眼治疗。