Mechanisms of enhancer regulation in aging and age-related diseases

衰老和年龄相关疾病的增强子调节机制

• 批准号: 9977548
• 负责人: Lu Wang
• 金额: $ 9.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977548
• 关键词: 3-Dimensional; Acute; Age; Aging; Cells; Chromatin; Chronic; Data; Diet; Disease; Enhancers; Ensure; Epigenetic Process; Fatty Liver; Fatty acid glycerol esters; Fibroblasts; Foundations; Future; Gene Expression; General Population; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Goals; Hepatocyte; Histone Acetylation; Human; Immune; Immunology; Inflammation; Inflammatory; Intervention; Knockout Mice; Light; Link; Liver; Liver diseases; Malignant Neoplasms; Maps; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Morbidity - disease rate; Mus; Oncogenic; Pathway interactions; Phase; Phenotype; Predisposition; Probability; Proliferating; Public Health; Regulation; Regulatory Pathway; Research; Secure; Signal Transduction; Source; Specificity; Stimulator of Interferon Genes; Stress; Structural Protein; Testing; Time; Tissues; Training; age related; career; career development; cell age; cell type; connectome; experience; functional decline; healthy aging; in vivo; insight; mortality; mouse model; new therapeutic target; non-alcoholic; normal aging; novel; programs; promoter; response; senescence; therapeutic target; transcription factor

PROJECT SUMMARY/ABSTRACT My overarching goal is to understand the three-dimensional (3D) enhancer regulation of aging and age-related diseases. Aging is accompanied by functional decline of tissues and an increased probability of many diseases. Epigenetic alteration is one hallmark of aging. Several lines of evidence demonstrate that histone acetylation levels elevate in senescent cells and global remodeling of the enhancer landscape occurs in aging and senescence. However, there is poor understanding of the influence of three-dimensional (3D) enhancer regulation changes during senescence. My preliminary data demonstrate that many enhancers connect together to form large clusters, termed hubs. The enhancers and promoters included in hubs are different between proliferation and senescence. The senescence-specific hubs ensure critical transcription programs for senescent phenotypes. However, how enhancer hubs change in response to stress and the mechanisms and functions of these alterations remain to be elucidated. The main goal of the proposed studies is to uncover mechanisms underlying the 3D regulation of enhancer hubs under different sources of stress during aging and age-related disease. I hypothesize that (1) during aging, key enhancers cluster together within hubs to regulate stress-specific gene expression programs; (2) two enhancer regulatory pathways exist during normal aging: one is cell intrinsic, and the other is cell extrinsic deriving from environmental inflammatory signals which accelerate the intrinsic pathway. In the mentored K99 phase (Aim 1), I will study epigenetic mechanisms regulating 3D enhancer hubs in senescence (Aim 1a) and test their generalization among different types of senescence (Aim 1b). Completion of these aims will set the stage for my independent research in aging and age-related metabolic disorder. In the R00 phase (Aim 2), in natural aging in liver, utilizing a unique mouse model, I will dissect the intrinsic enhancer regulatory pathway in hepatocytes and the extrinsic pathway stimulated by environmental inflammatory signals. This will provide potential targets to ameliorate age-related metabolic disorders in future direction of my independent lab. Ultimately, the proposed research will unveil new mechanisms underlying the interplay between inflammation and enhancer regulation in aging and provide novel therapeutic targets for age-related diseases. The career development and training components in K99 phase will expand my experience in aging, metabolism and immunology to provide a rich foundation for my successful transition to an independent career.

项目摘要/摘要 我的总体目标是了解衰老和与年龄相关的三维（3D）增强子调节 疾病。衰老伴随组织的功能下降，许多人的可能性增加 疾病。表观遗传学改变是衰老的标志。几条证据表明组蛋白 乙酰化水平在衰老细胞中升高和增强子景观的全局重塑发生在衰老中 和衰老。但是，对三维（3D）增强子的影响的理解很差 衰老期间的调节变化。我的初步数据表明许多增强剂连接 一起形成大型簇，称为集线器。枢纽中包含的增强剂和启动子是不同的 在增殖和衰老之间。衰老特异性枢纽可确保关键的转录程序 衰老表型。但是，增强子中心如何在压力和机制和机制以及 这些改变的功能尚待阐明。拟议研究的主要目标是发现 在不同的应力源下，在不同的应力源下，在3D调节期间对3D调节的机制 衰老和与年龄有关的疾病。我假设（1）在衰老期间，钥匙增强剂聚集在一起 集线器调节应力特异性基因表达程序； （2）在 正常衰老：一个是细胞固有的，另一个是来自环境炎症的细胞外部元素 加速固有途径的信号。在指导的K99阶段（AIM 1），我将研究表观遗传学 调节衰老中3D增强子枢纽的机制（AIM 1A）并测试其在 不同类型的衰老（AIM 1B）。这些目标的完成将为我的独立 衰老和与年龄相关的代谢障碍的研究。在R00阶段（AIM 2），在肝脏的自然衰老中， 利用唯一的鼠标模型，我将剖析肝细胞中的内在增强剂调节途径 环境炎症信号刺激的外部途径。这将为潜在的目标提供 在我的独立实验室的未来方向上改善与年龄有关的代谢障碍。最终，提议 研究将揭示炎症和增强子调节之间相互作用的新机制 在衰老中，为与年龄有关的疾病提供新的治疗靶标。职业发展和培训 K99阶段的组成部分将扩大我在衰老，代谢和免疫学方面的经验，以提供富人 我成功过渡到独立职业的基础。