Epigenetic Changes associated with Neurodegenerative Diseases

描述（由申请人提供）：许多基本的细胞过程受到表观遗传调节的影响，近年来，基于染色质的表观遗传机制成为衰老过程重要方面的基础已经变得很明显。然而，尽管年龄是神经退行性疾病（ND）的一个突出的危险因素，但关于表观遗传改变在ND机制中的作用的信息非常少，例如阿尔茨海默病（AD），帕金森氏痴呆（PD），额颞叶变性（FTLD）或肌萎缩侧索硬化症（ALS）。我们认为，详细的生物学，机械和分子的理解，改变人类ND的表观遗传因素，有希望提高对疾病发病机制的理解和开发新的治疗干预措施。该项目的目标是：（1）研究是否存在主要的表观遗传修饰（2）使用可从宾夕法尼亚神经退行性疾病研究中心（CNDR）获得的大量人类样品库，在不同ND的背景下研究组蛋白（组蛋白翻译后修饰）的变化，（2）使用我们的模型系统来发现ND疾病的基础的新的表观遗传修饰，和（3）使用ND模型测试在人ND中观察到的新变化的相关性。这项多PI和合作研究者工作的拟定研究将利用我们实验室关于表观遗传学和衰老（Berger，Bonini，约翰逊）、ND（Bonini，托雷斯和Trojanowski）以及通过染色质免疫沉淀法获得的全基因组数据的生成和生物信息学分析（Gregory，Wang，Berger）的互补和交叉兴趣。将我们的综合专业知识应用于分析CNDR ND脑样本的丰富收集，将在ND的表观遗传学领域开展一项重大的新工作。在更广泛的科学和医学界，这一努力将促进发现ND的表观遗传机制，为治疗ND的新见解和新临床方法提供基础。) 公共卫生相关性：年龄的增长是阿尔茨海默病和帕金森氏痴呆症等神经退行性疾病的主要风险因素，这些疾病给个人带来了巨大的痛苦和社会成本，但人们对衰老如何导致这些疾病知之甚少。最近，很明显，组织我们的基因并调节其活性的“染色质”结构的变化是衰老过程的关键方面。我们将研究神经退行性疾病患者大脑中染色质变化的确切性质，并测试这些变化如何干扰正常功能，从而为改善人类福祉的新类别诊断和治疗提供基础。)

DESCRIPTION (provided by applicant): Many fundamental cellular processes are affected by epigenetic modulation, and in recent years it has become evident that chromatin-based epigenetic mechanisms underlie important aspects of the aging process. However, despite the fact that age is a prominent risk factor in neurodegenerative disease (ND), there is remarkably little information on the role of epigenetic alterations in mechanisms of ND such as Alzheimer's disease (AD), Parkinson's dementia (PD), frontotemporal degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). We believe that a detailed biological, mechanistic and molecular understanding of the epigenetic factors that are altered in human ND holds promise for an improved understanding of disease pathogenesis and for the development of novel therapeutic interventions. The goals of this Project are to: (1) investigate whether major epigenetic modifications (histone post-translational modifications) change in the context of different NDs using an extensive bank of human samples available from the Penn Center for Neurodegenerative Disease Research (CNDR), (2) use our model systems to discover new epigenetic modifications that underlie ND disease, and (3) test the relevance of novel changes seen in human ND using models of ND. The proposed studies of this multiple-PI and co-Investigator effort will leverage complementary and intersecting interests from our laboratories concerning epigenetics and aging (Berger, Bonini, Johnson), ND (Bonini, Torres and Trojanowski), and the generation and bioinformatic analysis of genome-wide data obtained by chromatin immunoprecipitation followed by second generation sequencing (Gregory, Wang, Berger). The application of our combined expertise to the analysis of the rich collection of CNDR ND brain samples will launch a major new effort in the field of epigenetics in ND. In the broader scientific and medical communities, this effort will promote discoveries of epigenetic mechanisms of ND to provide the foundation for new insights and novel clinical approaches to treat ND. ) PUBLIC HEALTH RELEVANCE: Advancing age is a major risk factor for neurodegenerative diseases like Alzheimer's disease and Parkinson's dementia, diseases that exact enormous personal suffering and costs to society, yet little is known about precisely how aging contributes to these diseases. Recently it has become evident that changes in the structure called "chromatin", which organizes our genes and regulates their activity, underlie key aspects of the aging process. We will investigate the precise nature of chromatin changes in brains from people with neurodegenerative diseases, and test how these changes interfere with normal function, thus providing a basis for new classes of diagnostics and therapies that will improve human well-being. )