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

描述(申请人提供)：年龄相关性黄斑变性(AMD)是一种复杂的疾病，其中多种非遗传和遗传风险因素导致疾病发展的年龄相关的方式。衰老和吸烟是非遗传风险因素最明显的例子，两者都与氧化应激水平升高有关。遗传风险因素包括替代补体途径中基因的一组变异等位基因，等等。AMD研究的基本目标之一是了解非遗传因素如何与该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。在这个应用中，我们建议研究锰超氧化物歧化酶(SOD2)和补体因子H(CFH)野生型等位基因与年龄相关的表观遗传调节，这两个基因的变异等位基因与AMD的风险相关。Sod2是导致视网膜色素上皮(RPE)氧化应激的胞浆过氧化氢的主要来源，其表达受表观遗传调控。CFH是替代补体途径的主要抑制因子，其表达在转录水平上受氧化应激的调节，在翻译水平上受miR-146a的表观遗传调控。我们假设，调控SOD2和CFH野生型等位基因表达的非遗传机制会导致蛋白质浓度的变化，这与突变等位基因的基因产物的功能变化类似。这项工作的意义在于一个整合了遗传学、环境效应和衰老的假说。以这种方式探讨AMD的发病机制可能会导致更好地管理甚至预防这种疾病的新的临床方法。

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.