The Role of Histone Deacetylases in Age-related Macular Degeneration

组蛋白脱乙酰酶在年龄相关性黄斑变性中的作用

基本信息

批准号：
9904657
负责人：
Mark E Kleinman
金额：
$ 36.24万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904657
关键词：
Acetylation Address Affect Age Age related macular degeneration Animals Apoptosis Apoptotic Atrophic Biochemical Biological Biology Biology of Aging Cell Culture Techniques Cell Death Cells Cessation of life Chemicals Choroidal Neovascularization Chromatin Clinical Clinical Research Communities Complex DNA DNA Structure DNA sequencing Data Development Disease Down-Regulation Engineering Enzymes Epigenetic Process Experimental Models Expression Profiling Eye Foundations Functional disorder Gene Expression Gene Expression Regulation Gene Silencing Gene Targeting Genes Genetic Transcription Histone Acetylation Histone Deacetylase Histone Deacetylation Histones Human Immunofluorescence Immunologic In Situ Hybridization In Vitro Individual Inflammation Inflammatory Investigation Knowledge Lysine Malignant Neoplasms Mass Spectrum Analysis Measures Methylation Microglia Modality Modeling Modification Molecular Nerve Degeneration Nonexudative age-related macular degeneration Nucleosomes Oxidative Stress Pathogenesis Pathway interactions Pattern Pharmacology Phosphorylation Photoreceptors Pigment Epithelium of Eye Post-Translational Protein Processing Post-Translational Regulation Process Proteomics Regulation Reporting Research Retina Retinitis Pigmentosa Role Scientific Advances and Accomplishments Secondary to Signal Pathway Signal Transduction Stable Isotope Labeling Structure of retinal pigment epithelium Techniques Therapeutic Ubiquitination Valproic Acid Western Blotting Work Yeasts Zinc bioinformatics pipeline cancer cell career cell type chemokine chromatin immunoprecipitation chromatin remodeling combinatorial cytotoxic cytotoxicity effective therapy genetic signature genome-wide histone modification improved in vivo in vivo Model inhibitor/antagonist insight interest methyl group molecular array mouse model novel protein complex response retinal apoptosis small molecule targeted treatment therapeutic target transcriptome transcriptome sequencing web site

项目摘要

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.

项目概要：对表观遗传生物学的大多数科学理解是在发育和癌症领域。在我的早期职业生涯中在此期间，我一直在研究视网膜中促炎症信号传导的各种途径，最近发现了组蛋白的强大生化修饰能力，组蛋白是一种与 DNA 复合的蛋白质形成核小体，调节 AMD 中特定炎症因子的表达。引人注目的抑制组蛋白脱乙酰化可诱导促炎基因特征的变化提示该通路可能参与AMD的发病机制。初步数据证明在晚期干性 AMD 眼中，参与这些途径的关键酶的表达减少氧化应激实验模型。组蛋白脱乙酰化的抑制导致显着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脱乙酰酶在干性 AMD 和 RPE 细胞死亡发病机制中的表达和功能模型和关联体外研究。拟议的工作将直接解决基本的知识缺乏问题关于组蛋白脱乙酰酶在视网膜炎症和细胞死亡调节中的作用对于我们寻找干性 AMD 的有效靶向疗法至关重要。