EPIGENETIC AGING OF THE OXIDATIVE STRESS RESPONSE IN THE MOUSE RPE

小鼠 RPE 氧化应激反应的表观遗传老化

• 批准号: 7986159
• 负责人: Leonard Martin Hjelmeland
• 金额: $ 61.75万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986159
• 关键词: Affect; Affinity; Age; Age related macular degeneration; Age-Months; Aging; Autoimmune Diseases; Body Regions; Candidate Disease Gene; Cell Line; Cells; Choroid; Collection; Complex; CpG Islands; Cytosine; DBL Oncoprotein; DNA; Data; Development; Disease; Disease Progression; Disease susceptibility; Epigenetic Process; Exhibits; Eye diseases; Female; Formalin; Freezing; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Goals; Grant; Hereditary Disease; Human; Immunohistochemistry; Individual; Introns; Investigation; Laser Scanning Cytometry; Lasers; Lead; Link; Location; Malignant Neoplasms; Measures; Messenger RNA; Methods; Methylation; Microdissection; Modification; Mus; Nerve Degeneration; Normal tissue morphology; Oxidative Stress; Paraffin Embedding; Pathway interactions; Pattern; Population; Proteins; RNA; Reactive Oxygen Species; Regulation; Reporter; Research; Retinal Degeneration; Retinal Pigments; Risk; Risk Factors; Role; SOD2 gene; Sampling; Structure of retinal pigment epithelium; Testing; Tissues; Tumor Suppressor Genes; Work; age related; base; biological adaptation to stress; bisulfite; cancer type; density; drug development; mRNA Expression; macula; male; novel strategies; promoter; protein expression; public health relevance; theories

DESCRIPTION (provided by applicant): Aging is the largest single risk factor for the development of complex genetic disease including cancer, autoimmune disease, and neurodegeneration (including age-related macular degeneration - AMD). The primary theory attempting to explain the role of aging in these diseases is focused on the macromolecular damage caused by reactive oxygen species (ROS) and the genetics of susceptibility to this damage. Complex genetic disease however can also be investigated from the perspective of epigenetics. Gene expression for many genes is epigenetically regulated as a function of age, and altered expression of these genes is potentially linked to the development and progression of disease. We hypothesize that age-related change in the expression of oxidative stress genes are the result of epigenetic changes in cytosine methylation in genomic DNA in the retinal pigment epithelium (RPE)/choroid. This type of methylation is the most common epigenetic modification of the genome. We will first measure the age-related change of the expression and cytosine methylation of a set of candidate genes in the mouse RPE/choroid which are linked to oxidative stress. The set includes Er1, Err1, Foxo3a, Nrf2, Pgc11, Prdx3, p66/Shc1, Sirt1, Sod2, Txn2, Txnrd2, and 14-3-38. Our preliminary data indicate that Prdx3, Sod2, and Txn2 may be epigenetically upregulated as a function of age. Next we will validate these results for SOD2 in the human RPE using fresh frozen and/or paraffin embedded tissue. The significance of this work is the development of a new approach to understanding the age-related risk for complex genetic disease in the retinal pigment epithelium. This approach will yield new targets for drug development and potential treatments which may enhance our current management of age-related macular degeneration (AMD). PUBLIC HEALTH RELEVANCE: This proposal outlines research on the epigenetics of age-related changes in the oxidative stress response in the mouse and human retinal pigment epithelium. The goal is to identify genes that may also be epigenetically regulated in human age-related retinal degeneration. The significance of this work is to provide a deeper understanding of how age is related to retinal degeneration, and the identification of new targets for drug development. This work will eventually lead to the development of individualized treatments for blinding eye diseases.

描述（由申请人提供）：衰老是发展复杂遗传疾病的最大单一风险因素，包括癌症、自身免疫性疾病和神经变性（包括年龄相关性黄斑变性- AMD）。试图解释衰老在这些疾病中的作用的主要理论集中在由活性氧（ROS）引起的大分子损伤和对这种损伤易感性的遗传学上。然而，复杂的遗传疾病也可以从表观遗传学的角度进行研究。许多基因的基因表达是作为年龄的函数进行表观遗传调节的，并且这些基因的改变的表达可能与疾病的发展和进展相关。我们推测，氧化应激基因表达的年龄相关变化是视网膜色素上皮（RPE）/脉络膜中基因组DNA胞嘧啶甲基化的表观遗传变化的结果。这种类型的甲基化是基因组最常见的表观遗传修饰。我们将首先测量小鼠RPE/脉络膜中与氧化应激相关的一组候选基因的表达和胞嘧啶甲基化的年龄相关变化。该组包括Er 1、Err 1、Foxo 3a、Nrf 2、Pgc 11、Prdx 3、p66/Shc 1、Sirt 1、Sod 2、Txn 2、Txnrd 2和14-3-38。我们的初步数据表明，Prdx 3，Sod 2和Txn 2可能作为年龄的函数在表观遗传学上上调。接下来，我们将使用新鲜冷冻和/或石蜡包埋的组织验证人RPE中SOD 2的这些结果。这项工作的意义在于开发了一种新的方法来了解视网膜色素上皮中复杂遗传疾病的年龄相关风险。这种方法将为药物开发和潜在治疗提供新的靶点，这可能会增强我们目前对年龄相关性黄斑变性（AMD）的管理。 公共卫生关系：该提案概述了小鼠和人类视网膜色素上皮细胞氧化应激反应中与年龄相关变化的表观遗传学研究。目标是确定在人类年龄相关性视网膜变性中也可能受到表观遗传调控的基因。这项工作的意义在于更深入地了解年龄与视网膜变性的关系，并确定药物开发的新靶点。这项工作将最终导致失明眼病的个体化治疗的发展。

项目成果

Potential therapeutic approaches for modulating expression and accumulation of defective lamin A in laminopathies and age-related diseases.

• DOI: 10.1007/s00109-012-0962-4
• 发表时间: 2012-12
• 期刊: JOURNAL OF MOLECULAR MEDICINE-JMM
• 影响因子: 4.7
• 作者: Zhavoronkov, Alex;Smit-McBride, Zeljka;Guinan, Kieran J.;Litovchenko, Maria;Moskalev, Alexey
• 通讯作者: Moskalev, Alexey