Age-related epigenetic gene silencing in the RPE

RPE 中与年龄相关的表观遗传基因沉默

• 批准号: 7138505
• 负责人: Leonard Martin Hjelmeland
• 金额: $ 22.79万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7138505
• 关键词: aging; epigenetics; gene induction /repression; genes; methylation

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a complex disease caused by ageing, genetics, and the environment. While the genetics and environmental causes of AMD are being vigorously pursued, the exact role of ageing in AMD is neither well understood nor well studied. In other complex age-related diseases such as atherosclerosis and cancer, epigenetics is providing a basic understanding of how age contributes to disease development. Epigenetics is the study of long term covalent modification of the genome of somatic cells. These changes do not involve alterations in gene sequence and are therefore not mutations. Methylation of gene promoters at CG dinucleotide rich regions (CpG islands) is a major epigenetic modification leading to gene silencing. These changes occur in single cells as a stochastic process resulting in significant heterogeneity in populations of cells which are otherwise genetically identical. We hypothesize that genes functioning as suppressors of neurodegeneration, oxidative stress, or angiogenesis are silenced in the retinal pigment epithelium (RPE) as a function of age by epigenetic mechanisms. These changes are heterogeneous within the population of RPE cells leading to heterogeneous effects on the adjacent photoreceptors, Bruch's membrane, and choriocapillaris. To test this hypothesis, we will focus our initial studies on TIMP3, BRCA1, IGF2, and GSTP1. We have shown that the expression at the mRNA level of all four genes is downregulated with age in the RPE/choroid of the mouse. All four genes also have functions potentially related to AMD. TIMP3 is an angiogenesis inhibitor, BRCA1 and GSTP1 are suppressors of oxidative stress, and IGF2 is a trophic factor. Finally, the promoters of these genes all have CpG islands in the mouse and exhibit age-related methylation in a variety of human epithelial tissues. We will first quantify the age-related decline of expression for these genes on a single cell basis in the mouse RPE. Next we will investigate the age-related methylation of the promoters of these genes in whole mouse RPE/choroid. The successful completion of the these aims will establish epigenetics as an important new avenue for studying age-related changes in human RPE function as well as the technical ability to relate the epigenetic changes in individual RPE cells to localized areas of pathology.

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是一种由衰老、遗传和环境引起的复杂疾病。虽然人们正在大力研究 AMD 的遗传和环境原因，但衰老在 AMD 中的确切作用尚不清楚，也没有得到充分研究。在动脉粥样硬化和癌症等其他复杂的与年龄相关的疾病中，表观遗传学正在提供对年龄如何影响疾病发展的基本了解。表观遗传学是对体细胞基因组长期共价修饰的研究。这些变化不涉及基因序列的改变，因此不是突变。 CG 二核苷酸丰富区（CpG 岛）基因启动子的甲基化是导致基因沉默的主要表观遗传修饰。这些变化作为随机过程发生在单个细胞中，导致在其他方面遗传相同的细胞群体中存在显着的异质性。我们假设，作为神经退行性变、氧化应激或血管生成抑制因子的基因在视网膜色素上皮 (RPE) 中通过表观遗传机制随着年龄的增长而沉默。这些变化在 RPE 细胞群中是异质的，导致对相邻光感受器、布鲁赫膜和脉络膜毛细血管的异质影响。为了检验这一假设，我们将初步研究重点放在 TIMP3、BRCA1、IGF2 和 GSTP1 上。我们已经证明，在小鼠的 RPE/脉络膜中，所有四种基因的 mRNA 水平的表达随着年龄的增长而下调。所有四个基因都具有与 AMD 潜在相关的功能。 TIMP3 是一种血管生成抑制剂，BRCA1 和 GSTP1 是氧化应激抑制剂，IGF2 是一种营养因子。最后，这些基因的启动子在小鼠中均具有 CpG 岛，并在多种人类上皮组织中表现出与年龄相关的甲基化。我们将首先在小鼠 RPE 的单细胞基础上量化这些基因与年龄相关的表达下降。接下来我们将研究整个小鼠 RPE/脉络膜中这些基因启动子的年龄相关甲基化。这些目标的成功实现将使表观遗传学成为研究人类 RPE 功能与年龄相关的变化的重要新途径，以及将单个 RPE 细胞的表观遗传变化与局部病理区域联系起来的技术能力。