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; 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）：衰老是开发复杂遗传疾病（包括癌症，自身免疫性疾病和神经变性的）最大的单一危险因素（包括与年龄相关的黄斑变性-AMD）。试图解释衰老在这些疾病中的作用的主要理论集中于由活性氧（ROS）引起的大分子损害以及对这种损害的易感性的遗传学。然而，复杂的遗传疾病也可以从表观遗传学的角度研究。许多基因的基因表达在表观遗传学上是根据年龄的函数的，这些基因的表达改变可能与疾病的发展和进展有关。我们假设与年龄相关的氧化应激基因表达变化是视网膜色素上皮（RPE）/脉络膜中基因组DNA中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学修饰。我们将首先测量与氧化应激有关的小鼠RPE/脉络膜中一组候选基因表达和胞嘧啶甲基化的变化。该集合包括ER1，ERR1，FOXO3A，NRF2，PGC11，PRDX3，P66/SHC1，SIRT1，SOD2，TXN2，TXNRD2，TXNRD2和14-3-38。我们的初步数据表明，PRDX3，SOD2和TXN2可以表观上上调，这是年龄的函数。接下来，我们将使用新鲜的冷冻和/或石蜡嵌入的组织来验证人RPE中的SOD2。这项工作的意义是开发一种新方法，以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带来新的靶标，这可能会增强我们目前对年龄相关的黄斑变性（AMD）的管理。 公共卫生相关性：该提案概述了小鼠和人类视网膜色素上皮氧化应激反应变化的表观遗传学的研究。目的是确定在与人类年龄相关的视网膜变性中也可能在表观遗传调节的基因。这项工作的意义是对年龄与视网膜变性的关系以及对药物开发的新目标的识别提供更深入的了解。这项工作最终将导致开发针对盲目疾病的个性化治疗方法。