Epigenetics of Aging and Age-associated Diseases

衰老和年龄相关疾病的表观遗传学

基本信息

批准号：
8899394
负责人：
SHELLEY L BERGER
金额：
$ 164.01万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899394
关键词：
Accounting Acetylesterase Address Age Aging Animal Model Automobile Driving Behavior Biochemistry Cell Aging Cells Cellular biology Chromatin Chromatin Remodeling Factor Chromatin Structure Code Complex DNA DNA Methylation DNA Modification Process DNA Sequence DNA biosynthesis Data Deacetylation Development Diet Disease Down-Regulation Epigenetic Process Equilibrium Functional disorder Funding G-Quartets Genetic Genetic study Genome Genomics Goals Grant Health Heterochromatin Histones Human Knockout Mice Lead Leadership Link Longevity Manuscripts Mass Spectrum Analysis Methylation Modeling Molecular Molecular Chaperones Mus Non-Histone Chromosomal Proteins Nuclear Nuclear Lamin Nucleosomes Organism Pathology Pharmaceutical Preparations Pharmacotherapy Phenotype Post-Translational Protein Processing Process Proteins Publications Publishing Recombinants Regulation Role Site Structure Technology Telomerase Telomere Shortening Telomere-Binding Proteins Testing Time Tissues Translating Untranslated RNA Yeast Model System Yeasts base cell age cell injury combat drug discovery epigenome epigenomics genome-wide healthy aging histone modification human disease human tissue inhibitor/antagonist insight methylome mouse model novel programs senescence small molecule structural biology yeast genetics

项目摘要

DESCRIPTION (provided by applicant): Epigenetics is defined as heritable changes in genomic function and phenotype that do not involve alteration to DNA sequence. This higher level control of genome function is embodied in chromatin, a composite of nucleosomes (DNA and histones), as well as other non-histone proteins. Human disease is increasingly being linked to epigenetic and chromatin changes. The central hypothesis of this Program Project is that chromatin, as an inherently dynamic structure, is prone to age-associated degeneration, but that this degeneration is also countered by protective processes. This Program Project studies these age-associated chcomatin changes as they occur in the context of cell senescence, an irreversible proliferation arrest of damaged cells that contributes to tissue aging. Our studies from the first cycle of funding confirmed the previously suspected role for epigenetics as a critical determinant of aging and longevity. As a cross-disciplinary and highly collaborative team (46 manuscripts to date [published or submitted] in the 2008-2013 funding cycle, of which 19 are collaborative), we will continue to employ biochemistry, structural biology, cell biology, yeas genetics, and state-of-the-art epigenomic technologies in yeast and human cells to elucidate the role of epigenetics in aging and senescence. In particular, we will define degenerative and protective changes to chromatin, and the molecular mechanisms underlying them. The relevance of these studies for aging will be tested by reference to young and old human tissues and in mouse models, assessing phenotypes of aging. Moreover, based on our findings from the first cycle of funding, we have already initiated efforts to leverage our mechanistic insights into lead compounds for novel therapies to promote healthy aging. Our ultimate goal is to understand the balance of processes that culminate in age-associated chromatin dysfunction, so that we can devise strategies to manipulate the balance to promote healthy aging.

描述（由申请人提供）：表观遗传学被定义为不涉及对DNA序列改变的基因组功能和表型的可遗传变化。这种对基因组功能的更高水平的控制体现在染色质中，染色质是核小体（DNA和组蛋白）以及其他非固定蛋白的复合物。人类疾病越来越多地与表观遗传和染色质变化有关。该程序项目的中心假设是，染色质作为固有的动态结构，容易出现与年龄相关的变性，但这种变性也被保护过程所抵消。该计划项目研究了这些与年龄相关的chcomatin在细胞衰老的情况下发生的变化，这是导致组织衰老的受损细胞的不可逆增殖停滞。我们从第一个资金周期开始的研究证实了先前怀疑的表观遗传学的作用，这是衰老和寿命的关键决定因素。作为一个跨学科和高度协作的团队（迄今为止有46项手稿[在2008 - 2013年的融资周期中发表或提交]，其中19个是协作的），我们将继续使用生物化学，结构生物学，生物学，YEAS生物学，YEAS遗传学，YEAS遗传学，以及现状的表观学技术和人类的表现力学和人类的表现。特别是，我们将定义染色质的退化性和保护性变化，以及它们的分子机制。这些研究对于衰老的相关性将通过参考年轻人和旧人类组织和小鼠模型来测试，从而评估衰老的表型。此外，根据我们从第一个资金周期开始的发现，我们已经开始努力，以利用机械洞察力对新型疗法的铅化合物来促进健康的衰老。我们的最终目标是了解最终在与年龄相关的染色质功能障碍中的过程平衡，以便我们可以制定策略来操纵平衡以促进健康的衰老。