EPIGENETIC AGING OF THE OXIDATIVE STRESS RESPONSE IN THE MOUSE RPE

描述（由申请人提供）：衰老是复杂遗传疾病发展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受表观遗传调控，作为年龄的一种功能，这些基因表达的改变可能与疾病的发生和进展有关。我们假设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。该集合包括Er1、Err1、Foxo3a、Nrf2、Pgc11、Prdx3、p66/Shc1、Sirt1、Sod2、Txn2、Txnrd2、14-3-38。我们的初步数据表明，Prdx3、Sod2和Txn2可能随着年龄的增长而表观遗传上调。接下来，我们将使用新鲜冷冻和/或石蜡包埋组织验证人类RPE中SOD2的这些结果。这项工作的意义在于开发了一种新的方法来理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。

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.