Epigenetic Regulation of Gene Expression in the Aging Eye

衰老眼睛基因表达的表观遗传调控

• 批准号: 9040962
• 负责人: Vikki Marie Weake
• 金额: $ 38.17万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040962
• 关键词: Acetyltransferase; Age; Age related macular degeneration; Aging; Biological Aging; Biological Models; Cell Aging; Cell Culture Techniques; Cells; Chromatin; Complex; Data; Defect; Diabetic Retinopathy; Disease; Drosophila genus; Epigenetic Process; Exhibits; Eye; Eye Development; Eye diseases; Gene Expression; Genetic; Genetic Transcription; Goals; Health; Heterochromatin; Histone Acetylation; Histones; Human; Individual; Inherited; Lead; Light; Longevity; Modeling; Mus; Mutate; Mutation; Nature; Onset of illness; Orthologous Gene; Pathogenesis; Patients; Phenotype; Photoreceptors; Play; Proteins; RNA Interference; Recovery; Research; Retinal Degeneration; Retinitis Pigmentosa; Rhodopsin; Role; Severities; Stress; System; Testing; Therapeutic Intervention; Tissues; Transcriptional Activation; Type 7 Spinocerebellar Ataxia; Variant; Vision; Work; activating transcription factor; age related; chromatin modification; chromatin remodeling; epigenetic regulation; genetic manipulation; genome-wide; histone methylation; mutant; novel; photoreceptor degeneration; prevent; programs; targeted treatment; tool

 DESCRIPTION (provided by applicant): An important question in determining the intersection of aging and biological mechanisms of eye diseases is whether age-related changes in epigenetic processes drive the transition from aging to early disease state in ocular diseases of aging such as age-related macular degeneration. During aging and the pathogenesis of ocular disease, significant changes in chromatin correlate with, and contribute to, misregulation of gene expression. It is therefore important to understand how epigenetic processes contribute to age-dependent changes in gene expression and visual function in the eye, so that effective therapeutic interventions for late- onset retinal degenerative diseases can be developed. The long-term goal is to elucidate the underlying epigenetic processes that contribute to aging in the eye, and that can be targeted to restore youthful transcriptional programs and thus prevent the transition from aging to ocular disease. The objective of this application is to identify the epigenetic mechanisms that contribute to aging in photoreceptors using Drosophila - an excellent model for both epigenetics and aging due to its short life-span and amenability to genetic manipulation. The central hypothesis is that stochastic defects in epigenetic processes that activate transcription contribute to age-related decreases in photoreceptor gene expression and loss of visual function. This hypothesis is highly relevant to age-related ocular diseases in humans because it supports a model in which modest defects in transcriptional activation lead to a reduction in the levels of key proteins in individual photoreceptor cells within the eye, leading to progressive defects in visual function and eventual photoreceptor degeneration. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Characterize the contribution of epigenetic activation to age-dependent transcriptional changes in photoreceptors; and 2) Identify the epigenetic factors that maintain active transcription in aging photoreceptors. Under the first aim, genome-wide and single-cell approaches will be used to determine the overlap between changes in gene expression and chromatin modifications that result from aging, and changes that result from misregulation of specific epigenetic processes that activate transcription such as histone acetylation and histone deubiquitylation. Under the second aim, an age-dependent defect in the ability of photoreceptors to recover rhodopsin levels and localization following blue-light stress will be used as a sensitized system in which to identify epigenetic factors that are required to maintain active transcription in aging photoreceptors. The rationale for the proposed research is that its successful completion is expected to identify novel epigenetic targets for therapies to delay or prevent late-onset retinal degeneration. This research is significant because an understanding of these fundamental epigenetic mechanisms is critical to develop therapeutic interventions against ocular diseases associated with aging, in which epigenetic processes might contribute to disease onset, severity or progression.

 描述（由申请人提供）：在确定眼部疾病的衰老和生物学机制的交叉点时的一个重要问题是，表观遗传过程中的年龄相关变化是否驱动衰老性眼部疾病（如年龄相关性黄斑变性）从衰老转变为早期疾病状态。在衰老和眼病的发病过程中，染色质的显著变化与基因表达的失调相关，并有助于基因表达的失调。因此，重要的是理解表观遗传过程如何有助于眼睛中基因表达和视觉功能的年龄依赖性变化，从而可以开发针对迟发性视网膜变性疾病的有效治疗干预。长期目标是阐明导致眼睛衰老的潜在表观遗传过程，并且可以有针对性地恢复年轻的转录程序，从而防止从衰老到眼部疾病的转变。本申请的目的是确定表观遗传机制，有助于老化的光感受器使用果蝇-一个很好的模型，表观遗传学和老化，由于其寿命短，并服从遗传操作。核心假设是，表观遗传过程中激活转录的随机缺陷导致感光基因表达的年龄相关性降低和视觉功能丧失。这一假说与人类年龄相关性眼病高度相关，因为它支持一种模型，其中转录激活的适度缺陷导致眼内单个感光细胞中关键蛋白质水平的降低，导致视觉功能的进行性缺陷和最终的感光细胞变性。在强有力的初步数据的指导下，这一假设将通过追求两个具体目标进行测试：1）表征表观遗传激活对光感受器中年龄依赖性转录变化的贡献;以及2）识别维持老化光感受器中活性转录的表观遗传因子。在第一个目标下，全基因组和单细胞方法将用于确定基因表达变化和由衰老引起的染色质修饰之间的重叠，以及由激活转录的特定表观遗传过程（如组蛋白乙酰化和组蛋白去泛素化）的失调引起的变化。在第二个目标下，光感受器在蓝光应激后恢复视紫红质水平和定位的能力中的年龄依赖性缺陷将被用作敏化系统，在该敏化系统中识别维持老化光感受器中的活性转录所需的表观遗传因子。拟议研究的基本原理是，其成功完成有望确定新的表观遗传靶点，用于延迟或预防迟发性视网膜变性的治疗。这项研究意义重大，因为了解这些基本的表观遗传机制对于开发针对与衰老相关的眼部疾病的治疗干预至关重要，其中表观遗传过程可能导致疾病的发作，严重程度或进展。