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: 9248363
• 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/9248363
• 关键词: Age; Age related macular degeneration; Aging; Biological; Biological Models; Blindness; 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; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; 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; SAGA; Severities; Stress; System; Testing; Therapeutic Intervention; Tissues; Transcriptional Activation; Treatment Efficacy; Type 7 Spinocerebellar Ataxia; Variant; Vision; activating transcription factor; age related; chromatin modification; chromatin remodeling; epigenetic regulation; genetic manipulation; genome-wide; histone methylation; mutant; novel; photoreceptor degeneration; prevent; programs; public health relevance; targeted treatment; therapeutic evaluation; 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（由适用提供）：确定眼部疾病的衰老和生物学机制的相交的一个重要问题是，表观遗传过程中与年龄相关的变化是否会导致从衰老到早期疾病状态的转变，例如与年龄相关的黄斑变性。在老化和眼部疾病的发病机理期间，染色质的显着变化与基因表达的不正当相关并有助于。因此，重要的是要了解表观遗传过程如何促进眼睛中基因表达和视觉功能的年龄变化，以便可以开发出有效的常规变性疾病的有效治疗干预措施。长期的目标是阐明有助于衰老的潜在表观遗传过程，并且可以针对恢复年轻的转录程序，从而防止从衰老到眼科疾病的过渡。该应用是为了鉴定使用果蝇的表观遗传机制，这些机制有助于感光细胞的衰老 - 这是表观遗传学和衰老的出色模型，因为它的寿命短，并且对遗传操纵的态度。中心假设是，激活转录的表观遗传过程中的随机缺陷有助于与年龄相关的光感受器基因表达和视觉功能的丧失。该假设与人类中与年龄相关的眼部疾病高度相关，因为它支持一个模型，在该模型中，转录激活中适度的缺陷导致眼睛内单个光感受器细胞中关键蛋白的水平降低，从而导致视觉功能和最终光感受器变性的逐渐缺陷。在强大的初步数据的指导下，将通过追求两个具体目的来检验该假设：1）表征表观遗传激活对感光体的年龄依赖性转录变化的贡献； 2）确定在衰老感光体中保持主动转录的表观遗传因子。在第一个目标下，将使用全基因组和单细胞方法来确定基因表达的变化与衰老导致的染色质修饰的重叠，以及因激活组蛋白乙酰化和组蛋白去偶联性的特定表观遗传过程而导致的变化。在第二个目标下，光感受器恢复蓝光蛋白水平和蓝光应力后定位的能力的年龄依赖性缺陷将被用作敏感系统，在该系统中，识别在衰老感光体中维持活性转录所需的表观遗传因素。拟议的研究的理由是，预计其成功的完成将确定疗法的新型表观遗传靶标，以延迟或预防迟到的常规定义。这项研究很重要，因为对这些基本面的表观遗传机制的理解对于针对与衰老相关的眼部疾病的理论干预至关重要，在这种情况下，表观遗传过程可能有助于疾病的发作，严重程度或进展。