TriState SenNET (Lung and Heart) Tissue Map and Atlas consortium

TriState SenNET（肺和心脏）组织图谱和 Atlas 联盟

• 批准号: 10376488
• 负责人: TOREN FINKEL
• 金额: $ 270万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376488
• 关键词: Address; Age; Area; Atlases; Benchmarking; Biochemical; Biological; Biological Assay; Biological Markers; Biology; Cardiac Myocytes; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cells; Collaborations; Communication; Consent; DNA Damage; Data; Data Analyses; Disease; Elderly; Exhibits; Experimental Animal Model; Fingerprint; Functional disorder; Generations; Goals; Health; Heart; Heterogeneity; Human; Image; Impairment; In Situ; Individual; Infrastructure; Institution; Joints; Knowledge; Leadership; Link; Lung; Maps; Medical center; Mitochondria; Mitotic; Modeling; Molecular; Molecular Profiling; Morphology; Mutation; Neonatal; Neurons; Ohio; Oncogenes; Organ; Oxidative Stress; Phenotype; Physiological; Population; Procedures; Prognosis; Proliferating; Property; Proteomics; RNA; Research; Research Personnel; Resolution; Resources; Sampling; Slice; Standardization; Stimulus; Stress; Sum; Technology; Therapeutic; Tissue Sample; Tissues; United States National Institutes of Health; Universities; Vision; Withdrawal; XCL1 gene; age related; base; body system; cell type; cellular targeting; chromatin remodeling; computerized data processing; detection sensitivity; empowered; experience; functional outcomes; healthy aging; high throughput analysis; human tissue; innovation; innovative technologies; large datasets; medical schools; multimodality; neoplastic cell; novel; programs; proteotoxicity; response; secretory protein; senescence; synergism; telomere; tissue processing; tool development; transcriptomics; tumor

Senescent cells accumulate with age and are increasingly linked to a variety of age-related diseases. At present, senescent cells are operationally characterized based on a set of morphological, biochemical, and molecular properties. However, senescence is unlikely to represent a single uniform entity. Rather, analogous to what has been learned from studying tumors, the cell type, in conjunction with the specific endogenous driver of senescence, will likely determine the unique molecular fingerprint of a given senescent cell. Understanding this fingerprint, like our understanding of the specific genetic alterations in a given tumor, will, in turn, inform prognosis and response to therapy. Much of our understanding of the biology of senescence has come from experimental animal models, while our understanding of senescence in human cells and tissues remains, at best, incomplete. Similarly, while a number of exogenous stresses can trigger a senescent phenotype for cells in culture, the physiological relevant drivers of human senescence are not known. Finally, while for proliferating cells, senescence is characterized by a permanent withdrawal from the cell cycle, the relevant senescent cell markers and biology for critical post-mitotic cells (e.g., cardiac myocytes, neurons) is not well established. To begin to address these significant knowledge gaps, the TriState SenNet Tissue Mapping Center (TMC) will analyze human lung and heart tissue to provide a high-resolution map of the senescent cell population in these organs. With the combined expertise of the University of Pittsburgh and Carnegie Mellon University, Ohio State University, and the University of Rochester School of Medicine, this consortium will provide a comprehensive assessment of two organs linked to a variety of age-related diseases, one of which is largely post-mitotic. Our analysis will involve in situ mapping using established targeted assays, as well as high-content unbiased approaches involving single cell RNA/ATAC sequencing, proteomics, and spatial transcriptomics. In addition, as part of our mapping endeavor, the TriState SenNet TMC will analyze the relationship between the initiating trigger for senescence and the subsequent biology and phenotype of the senescent cell. This relationship will be probed using precision cut tissue sections from human lungs and hearts that will be perturbed ex vivo by specific senescent triggers. This procedure will allow us to increase the precision and sensitivity of detection and localization of senescent cells in the lung and heart. Finally, we will purify and isolate senescent and non- senescent cells from an individual donor lung and used these isogenic primary cells to deconvolute the physiologically relevant driver of human senescence and delineate the molecular basis for the observed selectivity of senolytic therapy. Together, this combined analysis of tissue and tissue slices/cells from the same individual will provide an unrivaled, unprecedented, in-depth, high-resolution map of the senescent cell population in the human lung and heart, define the physiological drivers of senescence, and provide a rational approach to understand the therapeutic potential of senolytic therapy.

衰老细胞随着年龄的增长而积累，并且与各种与年龄相关的疾病越来越相关。现在， 衰老细胞的操作特征是基于一系列形态学、生化和分子特征 特性。然而，衰老不太可能代表一个统一的实体。相反，类似于 通过研究肿瘤、细胞类型以及特定的内源性驱动因素，我们了解到 衰老，可能会确定给定衰老细胞的独特分子指纹。了解这一点 指纹，就像我们对特定肿瘤的特定基因改变的理解一样，反过来也将告知预后 以及对治疗的反应。我们对衰老生物学的大部分理解都来自实验 动物模型，而我们对人类细胞和组织衰老的理解充其量仍然是不完整的。 同样，虽然许多外源压力可以引发培养细胞的衰老表型， 人类衰老的生理相关驱动因素尚不清楚。最后，对于增殖细胞来说， 衰老的特点是永久退出细胞周期，相关的衰老细胞标志物 关键的有丝分裂后细胞（例如心肌细胞、神经元）的生物学尚未明确。开始 为了解决这些重大的知识差距，TriState SenNet 组织绘图中心 (TMC) 将分析 人类肺和心脏组织，以提供这些器官中衰老细胞群的高分辨率图谱。 凭借匹兹堡大学和俄亥俄州立大学卡内基梅隆大学的综合专业知识 大学和罗切斯特大学医学院，这个联盟将提供全面的 对与多种年龄相关疾病相关的两个器官进行评估，其中之一主要是有丝分裂后疾病。我们的 分析将涉及使用已建立的目标分析进行原位绘图，以及高内涵无偏见 涉及单细胞 RNA/ATAC 测序、蛋白质组学和空间转录组学的方法。此外，如 作为我们绘图工作的一部分，TriState SenNet TMC 将分析发起者之间的关系 衰老以及随后的衰老细胞的生物学和表型的触发因素。这种关系将 使用来自人肺和心脏的精密切割组织切片进行探测，这些组织切片将受到离体干扰 特定的衰老触发因素。该程序将使我们能够提高检测的精度和灵敏度 衰老细胞在肺和心脏中的定位。最后，我们将纯化和隔离衰老和非衰老的 来自单个供体肺的衰老细胞，并使用这些同基因原代细胞来解卷积 人类衰老的生理相关驱动因素并描绘了所观察到的分子基础 senolytic 治疗的选择性。总之，这种对来自同一组织和组织切片/细胞的组合分析 个人将提供无与伦比的、前所未有的、深入的、高分辨率的衰老细胞图谱 人类肺和心脏中的人口，定义衰老的生理驱动因素，并提供合理的 了解 senolytic 疗法的治疗潜力的方法。