Epigenetic Regulation of Gene Expression in the Aging Eye

 描述(申请人提供)：在确定衰老和眼病生物学机制的交集时，一个重要的问题是，在老年性黄斑变性等老年性眼病中，表观遗传过程中与年龄相关的变化是否会推动从衰老到早期疾病状态的转变。在衰老和眼部疾病的发病机制中，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，重要的是要了解表观遗传过程如何有助于眼睛中基因表达和视功能的年龄相关性变化，以便开发针对迟发性视网膜退行性疾病的有效治疗干预措施。长期目标是阐明导致眼睛老化的潜在表观遗传过程，并可以有针对性地恢复年轻的转录程序，从而防止从衰老向眼部疾病的转变。这项应用的目的是利用果蝇识别导致光感受器衰老的表观遗传学机制--果蝇是一种既适合表观遗传学又适合衰老的模型，因为它的寿命短，易于进行基因操作。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的减少和视觉功能的丧失。这一假说与人类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，转录激活的适度缺陷会导致眼睛内单个光感受器细胞中关键蛋白水平的降低，从而导致视觉功能的进行性缺陷和最终的光感受器退化。在强大的初步数据的指导下，这一假说将通过追求两个特定的目标来检验：1)表征表观遗传激活对光感受器年龄依赖性转录变化的贡献；2)确定在老化的光感受器中维持活跃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被用来确定由衰老引起的基因表达和染色质修饰的变化，以及由于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)的错误调控而产生的变化之间的重叠。在第二个目标下，光感受器在蓝光胁迫后恢复视紫红质水平和定位的能力与年龄相关的缺陷将被用作敏化系统，在该系统中将识别在老化的光感受器中维持活跃转录所需的表观遗传因子。这项拟议研究的基本原理是，它的成功完成有望为延缓或预防迟发性视网膜变性的治疗确定新的表观遗传学靶点。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措施至关重要，在这些疾病中，表观遗传过程可能有助于疾病的发生、严重程度或进展。

 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.