Epigenetic regulation of SOD2 and CFH gene expression in the aging RPE

衰老 RPE 中 SOD2 和 CFH 基因表达的表观遗传调控

• 批准号: 8328681
• 负责人: Leonard Martin Hjelmeland
• 金额: $ 58.86万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328681
• 关键词: Age; Age related macular degeneration; Aging; Alleles; Alternative Complement Pathway; Area; Autopsy; Boron; Cell Line; Cells; Choroid; Clinical; Complement Factor H; Complex; Cryoultramicrotomy; Development; Disease; Dissection; Enhancers; Environmental Risk Factor; Epigenetic Process; Eye; Fluorescence; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Human; Hydrogen Peroxide; Image; Immunofluorescence Immunologic; In Situ; In Vitro; Inbred BALB C Mice; Inflammation; Introns; Laser Scanning Cytometry; Lasers; Lead; Link; Manganese Superoxide Dismutase; Measures; Messenger RNA; Methylation; Molecular; Mus; NF-kappa B; Oxidative Stress; Pathogenesis; Pattern; Proteins; Regulation; Reporter; Research; Rest; Risk; Risk Factors; Risk Management; SOD2 gene; Scanning; Source; Structure of retinal pigment epithelium; Superoxide Dismutase; TNF gene; Testing; Transfection; Variant; Western Blotting; Work; age effect; age related; base; bisulfite; cigarette smoking; demethylation; disorder prevention; genetic risk factor; inhibitor/antagonist; juvenile animal; mRNA Expression; mutant; non-genetic; promoter; protein expression; research study

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a complex disease where multiple nongenetic and genetic risk factors lead to disease development in an age-related fashion. Aging and cigarette smoking are the clearest examples of nongenetic risk factors, and both have been linked to elevated levels of oxidative stress. Genetic risk factors include a set of variant alleles for genes in the alternative complement pathway, among others. One of the fundamental objectives in AMD research is to understand how nongenetic factors are integrated with the genetic basis of this disease. The epigenetic regulation of the genome is currently thought to be the molecular mechanism through which nongenetic factors have an effect. In this application, we propose to study the age-related epigenetic regulation of wild type alleles of manganese superoxide dismutase (SOD2) and complement factor H (CFH), two genes whose variant alleles are associated with the risk of AMD. SOD2 is the major source of cytosolic hydrogen peroxide which leads to oxidative stress in the retinal pigment epithelium (RPE), and its expression is epigenetically regulated. CFH is a major inhibitor of the alternative complement pathway, whose expression is regulated by oxidative stress at the transcriptional level and epigenetically through miR-146a at the translational level. We hypothesize that nongenetic mechanisms regulating the expression of the wild type alleles of SOD2 and CFH lead to an alteration of protein concentration, which is similar to changes of function for the gene products of the mutant alleles. The significance of this work rests in a hypothesis which integrates genetics, environmental effects, and aging. Approaching the pathogenesis of AMD in this fashion may lead to new clinical approaches for better management or even prevention of the disease.

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是一种复杂的疾病，其中多种非遗传和遗传风险因素以与年龄相关的方式导致疾病发展。衰老和吸烟是最明显的非遗传风险因素的例子，两者都与氧化应激水平升高有关。遗传风险因素包括补体旁路途径中基因的一组变异等位基因等。AMD研究的基本目标之一是了解非遗传因素如何与这种疾病的遗传基础相结合。基因组的表观遗传调控目前被认为是非遗传因素发挥作用的分子机制。在本申请中，我们提出研究锰超氧化物歧化酶（SOD 2）和补体因子H（CFH）的野生型等位基因的年龄相关的表观遗传调节，这两个基因的变体等位基因与AMD的风险相关。SOD 2是导致视网膜色素上皮细胞（RPE）中氧化应激的细胞溶质过氧化氢的主要来源，其表达受表观遗传学调节。CFH是补体旁路途径的主要抑制剂，其表达在转录水平上受氧化应激调节，在翻译水平上通过miR-146 a表观遗传学调节。我们推测，非遗传机制调节的野生型等位基因的SOD 2和CFH的表达导致蛋白质浓度的改变，这是类似的突变等位基因的基因产物的功能的变化。这项工作的意义在于一个假设，它整合了遗传学，环境影响和衰老。以这种方式接近AMD的发病机制可能会导致新的临床方法，以更好地管理甚至预防该疾病。