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显然是衰老过程的重要方面。然而，尽管年龄是神经退行性疾病(ND)的重要危险因素，但关于表观遗传学改变在ND发病机制中的作用，如阿尔茨海默病(AD)、帕金森痴呆(PD)、额颞部变性(FTLD)或肌萎缩侧索硬化症(ALS)，信息却非常少。我们相信，对人类ND中改变的表观遗传因素的详细生物学、机制和分子理解有望改善对疾病发病机制的理解，并有助于开发新的治疗干预措施。该项目的目标是：(1)使用从宾夕法尼亚大学神经退行性疾病研究中心(CNDR)获得的大量人类样本库，调查主要的表观遗传修饰(组蛋白翻译后修饰)是否在不同的NDS的背景下发生变化，(2)使用我们的模型系统来发现ND疾病背后的新的表观遗传修饰，以及(3)使用ND的模型来测试在人类ND中所看到的新变化的相关性。这项多PI和联合调查员工作的拟议研究将利用我们实验室在表观遗传学和衰老(Berger，Bonini，Johnson)、ND(Bonini，Torres和Trojanowski)以及通过染色质免疫沉淀和第二代测序获得的全基因组数据的生成和生物信息学分析(Gregory，Wang，Berger)方面的互补和交叉兴趣。将我们的专业技术应用于分析丰富的CNDR ND脑样本，将在ND表观遗传学领域发起一项重大的新努力。在更广泛的科学界和医学界，这一努力将促进ND表观遗传学机制的发现，为治疗ND的新见解和新的临床方法提供基础。)

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. )