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基因组功能和表型的可遗传变化，不涉及 DNA 序列的改变。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）以及其他非组蛋白的复合物。人类疾病越来越多地与表观遗传和染色质变化相关。该计划项目的中心假设是，染色质作为一种固有的动态结构，容易发生与年龄相关的退化，但这种退化也可以通过保护过程来抵抗。该项目研究这些与年龄相关的 chcomatin 变化，因为它们发生在细胞衰老的背景下，细胞衰老是受损细胞不可逆的增殖停滞，导致组织衰老。我们从第一轮资助开始的研究证实了先前怀疑的表观遗传学作为衰老和长寿的关键决定因素的作用。作为一个跨学科和高度协作的团队（2008-2013 年资助周期中迄今为止[发表或提交]的 46 篇手稿，其中 19 篇是协作的），我们将继续采用生物化学、结构生物学、细胞生物学、耶斯遗传学、以及酵母和人类细胞中最先进的表观基因组技术，以阐明表观遗传学在衰老和衰老中的作用。特别是，我们将定义染色质的退行性和保护性变化及其背后的分子机制。这些研究与衰老的相关性将通过参考年轻和年老的人体组织和小鼠模型进行测试，评估衰老的表型。此外，根据我们在第一轮融资中的发现，我们已经开始努力利用我们对先导化合物的机制见解来开发新疗法，以促进健康老龄化。我们的最终目标是了解最终导致与年龄相关的染色质功能障碍的过程的平衡，以便我们能够制定策略来操纵平衡以促进健康衰老。