Histone and DNA methyltransferases in optic nerve regeneration

视神经再生中的组蛋白和 DNA 甲基转移酶

基本信息

批准号：
10432811
负责人：
Dong Feng Chen
金额：
$ 24.63万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432811
关键词：
ATAC-seq Adopted Adult Affect Aging Axon Blindness Cell Aging Cell Survival Chromatin Cre-LoxP DNA DNA Modification Methylases DNMT3a Deposition Development Disease Disease Progression Enhancers Epigenetic Process Event Eye diseases Failure Functional disorder Gene Expression Genes Glaucoma Growth Histones Homologous Gene In Vitro Injury Knock-out Knockout Mice Knowledge Laboratories Lead Link Mammals Methylation Methyltransferase Microspheres Modeling Modification Molecular Mus Natural regeneration Nerve Crush Nerve Regeneration Nervous System Trauma Neuraxis Neurites Neurodegenerative Disorders Neurons Optic Nerve Optic Nerve Injuries Patients Persons Pilot Projects Regenerative capacity Research Retina Retinal Diseases Retinal Ganglion Cells Role System Testing Transposase Vision Work age related axon growth cell growth clinically relevant epigenomics histone methyltransferase in vivo in vivo regeneration injury recovery loss of function member methyl group nerve damage nerve repair neural growth neurite growth novel therapeutic intervention optic nerve disorder optic nerve regeneration postnatal programs regenerative relating to nervous system retinal ganglion cell degeneration retinogenesis sight restoration small molecule stem cells transcriptome sequencing transcriptomics

项目摘要

Project summary Mature neurons in the central nervous system of adult mammals, including retinal ganglion cells (RGCs) whose axons form the optic nerve, are incapable of regenerating. This presents a major challenge to restoring vision in patients with optic nerve injury or diseases, such as glaucoma, an optic nerve disease that affects 80 million people globally. Long-standing works from my laboratory demonstrate that optic nerve elongation is a programed event during development whose shut-down contributes critically to the failure of optic nerve regeneration. Potentially, epigenetic modification may reprogram neurons to regain this capacity by reactivating progenitor cell genes that have been silenced during neural maturation. Methylation, a key epigenetic mechanism carried out by histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), is essential in retinogenesis. Increased levels of methylation and methyltransferases activity is highly correlated with aging and retinal diseases progression. However, the functional role of epigenetic factors HMTs and DNMTs in RGC degeneration, or glaucoma in general, is unclear. By examining specific epigenetic changes associated with RGCs in mouse, we recently detected dynamic expression of a major HMT, enhancer of zeste homolog 1 (Ezh1) and a key member of DNMTs, that inversely correlate with retinal neuritogenesis and the optic nerve regenerative capacity of RGCs. Importantly, our pilot study found that pan inhibition of Ezh1 or DNMTs by small-molecule compounds increased neurite outgrowth in primary RGCs in vitro, and mice carrying selective DNMT deficiency in RGCs promoted robust axon re-growth in vitro and in injured optic nerve in vivo. We hypothesized that resetting the developmental epigenetic program induced by Ezh1 or DNMTs promotes the regenerative capacity of the optic nerve. The hypothesis will be tested in two specific aims: (1) Exploit the molecular events by which Ezh1 and DNMTs regulate RGC neurite growth in vitro, and (2) Examine the role of Ezh1 or DNMTs in optic nerve growth in vivo. This study will advance our knowledge about the epigenetic modulation of neuritogenesis, with the potential of discovering novel therapeutic strategies against neurodegenerative diseases.

项目摘要成年哺乳动物中枢神经系统中的成熟神经元，包括视网膜神经节细胞（RGC）轴突形成视神经，无法再生。这给恢复视力带来了一个重大挑战视神经损伤或疾病的患者，例如青光眼，一种影响8000万的视神经疾病全球人。我的实验室的长期工作表明，视神经伸长是一个编程在开发过程中，其关闭的事件对视神经再生的失败产生了严重贡献。潜在地，表观遗传修饰可能会重新编程神经元，以通过重新激活祖细胞来恢复这种能力在神经成熟过程中一直保持沉默的基因。甲基化，一种关键的表观遗传机制通过组蛋白甲基转移酶（HMTS）和DNA甲基转移酶（DNMT）在视网膜生成中至关重要。甲基化和甲基转移酶活性的水平增加与衰老和视网膜高度相关疾病进展。但是，表观遗传因子HMT和DNMT在RGC中的功能作用堕落或青光眼通常不清楚。通过检查与 RGC在小鼠中，我们最近检测到主要HMT的动态表达，Zeste同源物1（EZH1）的增强子以及DNMT的关键成员，与视网膜神经发生和视神经再生成反比 RGC的能力。重要的是，我们的试点研究发现，小分子对EZH1或DNMT的抑制作用化合物在体外原发性RGC中的神经突生长增加，而携带选择性DNMT缺乏的小鼠在RGC中，体内促进了稳健的轴突重新增长和受伤的视神经。我们假设了这一点重置EZH1或DNMT引起的发育表观遗传学计划促进再生能力视神经。该假设将以两个具体的目的进行检验：（1）利用分子事件 EZH1和DNMTS在体外调节RGC神经突的生长，（2）检查EZH1或DNMT在光学中的作用体内神经生长。这项研究将促进我们对神经发生的表观遗传调节的了解，有可能发现针对神经退行性疾病的新型治疗策略。