Epigenetic Changes with Age in Hematopoietic Stem Cells

造血干细胞随年龄的表观遗传变化

• 批准号: 7939579
• 负责人: Gretchen J. Darlington
• 金额: $ 122.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939579
• 关键词: Age; Aging; Animals; Cells; Characteristics; Chromatin; Communities; Cytidine; DNA; DNA Methylation; DNA Sequence; Data; Development; Discrimination; Epigenetic Process; Exhibits; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic Transcription; Global Change; Goals; Grant; Guidelines; Hematopoietic stem cells; Human Resources; IGF1 gene; Individual; Laboratories; Life; Liver; Longevity; Maps; Medicine; Methylation; Modeling; Mus; Nucleotides; Pathway interactions; Premature aging syndrome; Process; Protein p53; Repression; Research Personnel; Resources; Role; Site; Stem cells; Testing; Transplantation; Wild Type Mouse; Work; age related; bisulfite; chromatin modification; college; genome-wide; growth hormone-releasing hormone receptor; high throughput technology; interest; meetings; melanocyte; mouse model; multidisciplinary; mutant; programs; public health relevance; stem

DESCRIPTION (provided by applicant): Alterations in the epigenome have been shown to be a layer of regulation of gene expression in development and differentiation. Both chromatin modifications and DNA methylation are important in these processes. Relatively little is known about these changes in aging, but from studies done in the laboratory of one of the Co-PIs (EM), alterations in the liver and in melanocytes with age have been documented. This application brings together a multi- disciplinary team to generate a global, genome wide map of chromatin modifications associated with both activation and repression of gene expression as well as a global map of cytidine methylation sites in the DNA. DNA methylation has been shown to have more of a correlation with chromatin modifications than with specific DNA sequence. We propose to carry out these studies on murine hematopoietic stem cells (HSC) which have been shown by the Co-PI (MG) to have significant changes in gene expression between young and old mice as well as reduced ability to engraft upon transplantation to lethally irradiated recipients. The maps will be generated using high throughput sequencing which gives nucleotide level discrimination. Further, to test the role of the IGF1 pathway in chromatin modification, we will examine the HSC from a long lived mouse model, the growth hormone releasing hormone receptor mutant, the Little mouse. In addition, a second model of interest to the aging community that will be studied is the premature aging syndrome in which the p53 protein is stabilized and the animals have a shortened lifespan with accelerated characteristics of aging. Data generated from these studies will be a resource for the aging community and will be made available to the scientific community through the NCBI Gene Expression Omnibus site. This grant will enable the recruitment of four new personnel and can be completed within two years thus fulfilling one of the goals of the ARRA program. PUBLIC HEALTH RELEVANCE: This application will generate data on the epigenome of hematopoietic stem cells with age which will be released to the scientific community immediately. This project requires high throughput technology and a team of multidisciplinary investigators. The grant will respond to the ARRA guidelines by employing four individuals not currently working in the laboratories of the investigators.

描述（由申请人提供）：表观基因组的改变已被证明是发育和分化过程中基因表达的一层调节。染色质修饰和 DNA 甲基化在这些过程中都很重要。人们对衰老过程中的这些变化知之甚少，但根据其中一位 Co-PI (EM) 实验室进行的研究，已经记录了肝脏和黑素细胞随年龄的变化。该应用程序汇集了多学科团队，生成与基因表达的激活和抑制相关的染色质修饰的全球全基因组图谱，以及 DNA 中胞苷甲基化位点的全球图谱。 DNA 甲基化已被证明与染色质修饰的相关性大于与特定 DNA 序列的相关性。我们建议对小鼠造血干细胞（HSC）进行这些研究，Co-PI（MG）已表明这些细胞在年轻和年老小鼠之间的基因表达发生显着变化，并且在致命性移植后移植能力降低受辐射的接受者。这些图谱将使用高通量测序生成，从而提供核苷酸水平区分。此外，为了测试 IGF1 通路在染色质修饰中的作用，我们将检查来自长寿小鼠模型（生长激素释放激素受体突变体“小小鼠”）的 HSC。此外，老龄界将要研究的第二个模型是早衰综合症，其中p53蛋白稳定，动物寿命缩短，并具有加速衰老的特征。这些研究产生的数据将成为老龄化界的资源，并将通过 NCBI 基因表达综合网站向科学界提供。这笔赠款将能够招聘四名新人员，并可在两年内完成，从而实现 ARRA 计划的目标之一。 公共健康相关性：该应用程序将生成有关造血干细胞随年龄变化的表观基因组的数据，这些数据将立即发布给科学界。该项目需要高通量技术和多学科研究人员团队。这笔赠款将响应 ARRA 指南，雇用四名目前不在研究人员实验室工作的人员。