The Role of Histone Deacetylases in Age-related Macular Degeneration

项目摘要： 对表观遗传生物学的最科学的理解是在发育和癌症领域。在我早期的职业生涯中 期间，我一直在研究视网膜中促炎信号的各种途径，最近 发现了对组蛋白进行生物化学修饰的强大能力，组蛋白是一种与DNA复合的蛋白质， 形成核小体，以调节AMD中发现的特定炎症因子的表达。撞击 可通过抑制组蛋白脱乙酰化诱导的促炎基因特征的变化 提示该通路可能参与AMD的发病机制。初步数据显示， 在晚期干性AMD眼和老年性黄斑变性眼中， 氧化应激的实验模型。抑制组蛋白去乙酰化导致显著的细胞毒性， 对视网膜色素上皮的影响。在这个项目中，我计划严格剖析组蛋白的作用， 使用新型小鼠研究干性AMD和RPE细胞死亡发病机制中脱乙酰酶的表达和功能 模型和相关的体外研究。拟议的工作将直接解决知识的根本缺乏问题 组蛋白去乙酰化酶在视网膜炎症和细胞死亡调节中的作用， 在我们寻找有效的干性AMD靶向治疗方法中至关重要。

Project Summary: Most scientific understanding of epigenetic biology is in the field of development and cancer. In my early career period, I have been investigating various pathways of pro-inflammatory signaling in the retina and have recently discovered a powerful ability for biochemical modification of histones, a protein that complexes with DNA to form the nucleosome, to regulate the expression of specific inflammatory factors found in AMD. The striking changes in pro-inflammatory gene signatures that can be induced by inhibiting deacetylation of histones suggest that this pathway may be involved in the pathogenesis of AMD. Preliminary data demonstrated decreased expression of critical enzymes involved in these pathways in advanced dry AMD eyes and in experimental models of oxidative stress. Inhibition of histone deacetylation resulted in significant cytotoxic effects on the retinal pigment epithelium. In this project, I plan to rigorously dissect the role of histone deacetylase expression and function in the pathogenesis of dry AMD and RPE cell death using a novel mouse model and correlate in vitro studies. The proposed work will directly address a fundamental lack of knowledge on the role of histone deacetylases in the regulation of retinal inflammation and cell death making the work underway critically important in our search for effective targeted therapeutics for dry AMD.