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：
8389546
负责人：
ROBERT N WEINREB
金额：
$ 59.6万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389546
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 Diet 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

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.

抽象的该提议解决了以下想法：sirtuin-1（sirt1）的激活，一种可以调节的乙酰基酶基因表达将增加视网膜神经节细胞（RGC）的存活率和视觉系统功能青光眼。 SIRT1的激活对于热量限制引起的年龄相关的降低至关重要发病率和寿命的增加。这种酶对新陈代谢，线粒体发挥作用功能，以及其他细胞功能主要通过组蛋白和其他蛋白质的脱乙酰化。热量 SIRT1的限制诱导的保护针对正常年龄相关的视网膜神经节细胞损失激活表明Sirtuins与青光眼高度相关。越来越多的证据表明热量限制的有益的好处（尽管不是全部）可以通过喂养来诱导用白藜芦醇（一种sirtuin活化剂和天然化合物）富含某些食物，包括红酒和花生。我们的总体假设是，增加的SIRT1激活将防止青光眼模型的视网膜，视神经和大脑中的青光眼损伤。我们的一般方法将是研究通过热量限制增加SIRT1激活的效果或通过补充饮食中的白藜芦醇并通过使用转基因来识别SIRT1的作用在RGC中缺乏SIRT1表达的小鼠。具体目标是：1）确定是否SIRT1 激活将减少视神经后THY-1基因表达和RGC死亡的RGC丧失受伤; 2）通过评估视网膜来确定SIRT1介导的RGC保护的生物学基础脂质过氧化，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）与基因调节非常重要； 3）确定是否 SIRT1激活保留了中央视觉系统途径的结构完整性和功能。