Using cellular co-biosis and age programmable mice to derive a global interaction map of aging hallmarks

使用细胞共生和年龄可编程小鼠来得出衰老标志的全局相互作用图

• 批准号: 10721454
• 负责人: DAVID A. SINCLAIR
• 金额: $ 45.36万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721454
• 关键词: 3-Dimensional; ATAC-seq; Acceleration; Affect; Age; Aging; Appearance; Architecture; Attenuated; Biological; Biology; Categories; Cell Nucleus; Cell physiology; Cells; Complex; Computer software; Cytoplasm; DNA; DNA Methylation; DNA methylation profiling; Data; Disease; Ensure; Epigenetic Process; Feedback; Female; Genetic; Genetic Variation; Genome; Genome Mappings; Genomic Segment; Health; Human; Hybrids; Image; Impairment; Incidence; Individual; Instruction; Intervention; Knowledge; Machine Learning; Mammals; Maps; Measures; Mitochondria; Monitor; Mus; Nuclear; Organ; Physiological; Process; RNA; Reporter; Reporting; Structure; System; Technology; Testing; Time; Tissue Harvesting; Tissues; Work; age related; aged; attenuation; biological systems; cell type; demethylation; epigenome; epigenomics; in vivo; indexing; inducible gene expression; innovation; insight; live cell imaging; male; methylation pattern; multiple omics; novel; pathological aging; programs; sensor technology; siRNA delivery; single-cell RNA sequencing; software development; time use; tool; ultra high resolution

PROJECT SUMMARY Biological systems are presumed to fail over time based on nine “hallmarks of aging,” which somehow cause a global decline in tissue function and health. Based on this paradigm, interventions, and combinations of them, are being developed to attenuate each of the hallmarks and slow the aging process. Unfortunately, a lack of insight into the interdependence among these aging hallmarks has made it difficult to develop universally effective mitigation strategies. Our lab and others have provided evidence that a loss of stored information impairs the function of cellular machinery and physical structures, leading to aging and age-related diseases. We have developed the ICE system (Yang et al. 2022, provisionally accepted by Cell) which allows for spatial and temporal control over epigenetic aging in mammals. We have also discovered that partial reprogramming using the reprogramming factors, Oct4, Sox2, and Klf4 (OSK), allows cells to retrieve a “backup copy” of youthful information that resets the epigenome, reverses multiple hallmarks of aging, and restores DNA methylation patterns to their previous youthful state (Lu et al., 2020; Yang et al., 2022, provisionally accepted by Cell). In this study, we leverage our ability to control the pace of aging in forward and reverse directions to test the hypothesis that a loss of interconnectivity between cellular information and cellular machinery and physical structures is a primary driver of the Hallmarks of Aging and a reversible cause of aging itself. To do this, we will develop the first set of fluorescent hallmark reporters to monitor hallmark progression and interactions during aging and discover ways to promote their co-reversal. This novel tool will be utilized along with advanced multi- omic approaches in novel co-biosis systems and age-programmable mice in the heterogeneous UM-HET3 genetic background. This study is important because it will provide valuable knowledge concerning the long-standing questions about interconnectivity among the aging hallmarks, such as whether hierarchies exist and if the reversal of one hallmark ensures the erasure of others. Together, this work will provide the field with a novel set of customizable tools to track and study these hallmarks and test the hypothesis that many hallmarks intersect at the informational level and are therefore co-reversible when information in the nucleus is reset to a youthful state.

项目摘要 基于九个“衰老的标志”，生物系统随着时间的流逝而失败，这在某种程度上引起了 全球组织功能和健康下降。基于这种范式，干预措施和组合， 正在开发以衰减每个标志并减慢衰老过程。不幸的是，缺乏 对这些老化标志之间相互依赖性的见识使得很难普遍发展 有效的缓解策略。我们的实验室和其他人提供了证据表明丢失了存储的信息 损害细胞机制和物理结构的功能，导致衰老和年龄有关的疾病。 我们已经开发了冰系统（Yang等，2022，临时接受细胞），这允许空间 以及对哺乳动物表观遗传衰老的暂时控制。我们还发现了部分重编程 使用重编程因素OCT4，SOX2和KLF4（OSK）允许细胞检索年轻的“备份副本” 重置表观基因组，逆转多个衰老标志并恢复DNA甲基化的信息 他们以前的年轻状态的模式（Lu等，2020; Yang等，2022，被细胞临时接受）。 在这项研究中，我们利用了控制向前和反向方向上衰老节奏的能力，以测试 假设细胞信息与细胞机制与物理之间的互连丧失 结构是衰老标志的主要驱动力，也是衰老本身的可逆原因。为此，我们将 开发第一组荧光标志记者，以监视标志性进度和相互作用 衰老并发现促进其共逆转的方法。这个新颖的工具将与先进的多型工具一起使用 新型共生物病系统和可编程的小鼠在异质UM-HET3中的OMIC方法 遗传背景。 这项研究很重要，因为它将提供有关有关长期存在的有关有关的宝贵知识 老化标志之间的互连性，例如是否存在层次结构以及一个标志的逆转 确保擦除他人。这项工作将共同为该领域提供一套新颖的可自定义工具 跟踪和研究这些标志，并测试许多标志在信息层面相交的假设 因此，当核中的信息重置为年轻状态时，并且是可转换的。