Modeling the Aging Epigenome

衰老表观基因组建模

• 批准号: 8150336
• 负责人: Bruce A YANKNER
• 金额: $ 83.9万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150336
• 关键词: Address; Aging; Aging-Related Process; Animal Model; Biology of Aging; Brain; Caenorhabditis elegans; Cells; Chromatin; Complex; Degenerative Disorder; Development; Disease; Epigenetic Process; Gene Expression; Genetic; Global Change; Heart; Histones; Individual; Investigation; Lead; Longevity; Measures; Modeling; Molecular; Nematoda; Pancreas; Pathology; Physiology; Resolution; Risk; Role; Skeletal Muscle; System; Technology; Time; Tissues; Transgenic Mice; Transgenic Organisms; Work; abstracting; age related; base; cell type; chromatin immunoprecipitation; interest; mouse model; novel; novel strategies; promoter

DESCRIPTION Abstract: The role of global epigenetic changes in the aging process and age-related degenerative disorders is unknown. This proposal is based on the working hypothesis that specific cell types and tissues drive the aging process through global changes in the epigenome. To explore this hypothesis, we have conceived a novel system to address the methodological shortcomings that currently preclude cell-type-specific epigenetic analysis in complex tissues. The planned new approach, which we term Chromatin Isolation and Chromatin Immunoprecipitation (CI- ChIP), will involve transgenic expression of a tagged core histone in cells of interest using a cell type-specific promoter. The tagged histone would then be incorporated into the chromatin of the cells of interest, permitting the isolation of chromatin from specific cells in any animal model or complex tissue. We intend to use the nematode worm, Caenorhabditis elegans, to develop CI- ChIP. The genetic tractability and aging biology of the worm offers many advantages. Development of CI-ChIP would have immediate benefits for the study of gene expression and the epigenetics of aging in C. elegans. Furthermore, changes in gene expression during aging and under conditions that extend longevity could be measured at the tissue level for the first time. This will enable investigation of the molecular basis of differential rates of aging and the contribution of each of the major cell types in the worm. To explore the role of epigenetic changes in mammalian aging, CI-ChIP will be applied to transgenic mice expressing tagged histones targeted to tissues with pronounced age-related pathology, including the brain, heart, skeletal muscle, vasculature and pancreas. This would allow for global epigenetic analysis at cell type-specific resolution in any mouse model of disease, development or physiology. Finally, it is conceivable that CI-ChIP might lead to technology for predicting individuals at risk for age- related degenerative disorde

描述 抽象的： 整体表观遗传变化在衰老过程和与年龄相关的退行性疾病中的作用尚不清楚。该提议基于这样的工作假设：特定细胞类型和组织通过表观基因组的整体变化驱动衰老过程。为了探索这一假设，我们构想了一种新的系统来解决目前无法在复杂组织中进行细胞类型特异性表观遗传分析的方法学缺陷。计划中的新方法，我们称之为染色质分离和染色质免疫沉淀（CI-ChIP），将涉及使用细胞类型特异性启动子在感兴趣的细胞中转基因表达标记的核心组蛋白。然后，标记的组蛋白将被整合到感兴趣的细胞的染色质中，从而允许从任何动物模型或复杂组织中的特定细胞中分离染色质。我们打算使用线虫秀丽隐杆线虫来开发 CI-ChIP。线虫的遗传易驯化性和衰老生物学特性提供了许多优势。 CI-ChIP 的开发将为线虫基因表达和衰老表观遗传学的研究带来直接好处。此外，首次在组织水平上测量了衰老期间和延长寿命的条件下基因表达的变化。这将使研究不同衰老率的分子基础以及线虫中每种主要细胞类型的贡献成为可能。为了探索表观遗传变化在哺乳动物衰老中的作用，CI-ChIP 将应用于表达标记组蛋白的转基因小鼠，这些组蛋白针对具有明显年龄相关病理的组织，包括大脑、心脏、骨骼肌、脉管系统和胰腺。这将允许在任何疾病、发育或生理学小鼠模型中以细胞类型特异性分辨率进行全局表观遗传分析。最后，可以想象 CI-ChIP 可能会带来预测个体面临年龄相关退行性疾病风险的技术