Epigenetic Changes associated with Neurodegenerative Diseases

与神经退行性疾病相关的表观遗传变化

基本信息

批准号：
8889810
负责人：
SHELLEY L BERGER
金额：
$ 5.52万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889810
关键词：
Address Affect Age Aging Aging-Related Process Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antibodies Archives Area Astrocytes Bioinformatics Biological Biological Models Brain Cell physiology Cells Characteristics Chromatin Clinical Collection Communities Coupled DNA DNA Damage DNA Sequence Data Development Diagnostic Disease Disease model Drosophila genus Elderly Enzymes Epigenetic Process Euchromatin Fluorescent Probes Foundations Frequencies Frontotemporal Dementia Functional disorder Funding Gene Expression Gene Targeting Generations Genes Genome Goals Heterochromatin High-Throughput Nucleotide Sequencing Histone Acetylation Human Immunohistochemistry Individual Inflammation Laboratories Length Link Literature Maintenance Matrix Metalloproteinases Measures Medical Methylation Modeling Modification Molecular Nature Neurodegenerative Disorders Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathway interactions Patients Pennsylvania Personal Satisfaction Post-Translational Protein Processing Publishing Qualifying Research Research Personnel Resources Risk Factors Role Sampling Site-Directed Mutagenesis Societies Staging Structure Testing Therapeutic Tissues United States National Institutes of Health Universities aging brain base brain tissue cell type chromatin immunoprecipitation chromatin modification cost cytokine disorder control fly genome-wide genome-wide analysis histone modification improved insight interest normal aging novel novel therapeutic intervention polyglutamine response senescence success telomere transcriptome sequencing

项目摘要

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. )

描述（由申请人提供）：许多基本的细胞过程都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已成为衰老过程重要方面的基础。然而，尽管年龄是神经退行性疾病（ND）的一个重要危险因素，但关于表观遗传改变在阿尔茨海默病（AD）、帕金森痴呆（PD）、额颞叶变性等 ND 机制中的作用的信息却非常少。（FTLD）或肌萎缩侧索硬化症（ALS）。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开发新的治疗干预措施。该项目的目标是：(1) 使用宾夕法尼亚州神经退行性疾病研究中心 (CNDR) 提供的大量人类样本来研究主要表观遗传修饰（组蛋白翻译后修饰）在不同 ND 的背景下是否发生变化， (2) 使用我们的模型系统发现 ND 疾病背后的新表观遗传修饰，以及 (3) 使用 ND 模型测试人类 ND 中观察到的新变化的相关性。这项多 PI 和联合研究者工作的拟议研究将利用我们实验室关于表观遗传学和衰老（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（Gregory、Wang、Berger）。将我们综合的专业知识应用于分析丰富的 CNDR ND 大脑样本，将在 ND 表观遗传学领域发起一项重大的新努力。在更广泛的科学和医学界，这项工作将促进 ND 表观遗传机制的发现，为治疗 ND 的新见解和新临床方法奠定基础。）