Yale TMC for Cellular Senescence in Lymphoid Organs

耶鲁大学 TMC 研究淋巴器官细胞衰老

• 批准号: 10384399
• 负责人: Rong Fan
• 金额: $ 130万
• 依托单位: YALE UNIVERSITY
• 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/10384399
• 关键词: Adopted; Aging; Area; Atlases; Biological; Biological Markers; Biological Models; Biomedical Engineering; Bone Marrow; Cell Aging; Cell Cycle Arrest; Cell Proliferation; Cells; Collaborations; Communities; Computer software; Copyright; Data; Data Analytics; Development; Disease; Ensure; Environment; Fostering; Generations; Goals; Grant; Hematology; Hematopoiesis; Heterogeneity; Histopathology; Human; Image; Immune; Immunobiology; Informatics; Intervention; Kidney; Licensing; Liver; Longevity; Lung; Lymphoid Tissue; Maps; Metadata; Modeling; Molecular; Molecular Target; Motivation; Natural regeneration; Organ; Organoids; Phenotype; Physicians; Physiology; Play; Policies; Proteins; Publications; Published Comment; Publishing; Quality Control; Research; Research Activity; Resolution; Resource Sharing; Resources; Risk; Role; SCAP2 gene; Scientist; Specimen; Standardization; Stress; Techniques; Technology; Thymus Gland; Time; Tissues; Tonsil; Translating; United States National Institutes of Health; Validation; age related; analysis pipeline; cell type; data resource; data sharing; data submission; design; experience; functional disability; healthspan; human tissue; image visualization; immune function; improved; insight; lymph nodes; lymphoid organ; member; molecular imaging; multidisciplinary; new technology; programs; repaired; secondary lymphoid organ; senescence; single molecule; synergism; tertiary lymphoid organ; tool; transcriptome; transcriptomics; wound healing

PROJECT SUMMARY Cell senescence in human tissues is an irreversible cell cycle arrest state in otherwise proliferative cells, which is a hallmark of aging that alters the tissue environments via senescence-associated secretory phenotype (SASP) but may also play a beneficial role in tissue remodeling, regeneration, and wound healing. Lymphoid organs play a vital role in hematopoiesis and immune function. How cellular senescence in these tissues is associated with stress-induced or age-related functional impairment, what types or subtypes of senescent cells are present and their spatial heterogeneity and how these cells impact the tissue environments remain poorly understood, precluding the development of strategies to target senescent cells to improve healthspan/lifespan or harnessing these cells or secreted factors to promote tissue remodeling and repair. A recent commentary published in Cell by NIH identified five broad areas (atlases, imaging &visualization, biomarkers, model systems, perturbation and validation) that would help propel the field forward. Our application will assemble a multidisciplinary team to tackle all these areas and specifically, as a Tissue Mapping Center (TMC), will focus on generating the molecular and cellular maps of cellular senescence and associated tissue environments in 4 primary and secondary lymphoid organs. Specifically, it will (a) collect, analyze, annotate, and share high quality non-diseased human primary (bone marrow and thymus) and secondary (tonsil and lymph node) lymphoid tissues, (2) develop and deploy a suite of high-resolution, high-content and high-throughput single- cell & spatial omics technologies to characterize these specimens and paired biofluids, and (3) perform integrated informatics to identify biomarkers of senescent cell heterogeneity and to construct comprehensive molecular and cellular maps of cellular senescence and associated environments in these organs. Four major biological analysis pipelines are: (1) single-cell high-plex (>40) protein secretome profiling, (2) single-cell proteo-transcriptomic sequencing (scCITE-seq), (3) spatial proteo-transcriptomic sequencing at cellular level (DBiT-seq for co-mapping whole transcriptome and a panel of ~300 proteins at cellular level with 10µm pixel size), and (4) spatial molecular imaging (SMI) of ~1,000 molecular targets in FFPE tissues at single-molecule subcellular resolution. With these unique tools, we will (a) characterize functional SASP heterogeneity and identify biomarkers of SAPS in different cell types, (b) construct molecular and cellular maps in 4 human lymphoid tissues, and (c) identify biomarkers of cellular senescence in tissue and the associated environments, contributing to the resource building of SenNet. Since the immune function is central to the physiology of all major organs, our study will provide insights to the role of senescent immune cells in development, aging, or disease in other organs like gut, lung, liver, and kidney, representing a strong synergy within SenNet and the wider scientific community.

项目概要 人体组织中的细胞衰老是增殖细胞中不可逆的细胞周期停滞状态， 是衰老的标志，通过衰老相关的分泌表型改变组织环境 (SASP)，但也可能在组织重塑、再生和伤口愈合中发挥有益作用。 器官在造血和免疫功能中发挥着至关重要的作用。 与压力引起的或与年龄相关的功能障碍有关，衰老细胞的类型或亚型 存在，但它们的空间异质性以及这些细胞如何影响组织环境仍然很差 理解，妨碍制定针对衰老细胞以改善健康/寿命的策略 或利用这些细胞或分泌因子促进组织重塑和修复。 NIH 在《细胞》杂志上发表的文章确定了五个广泛的领域（图谱、成像和可视化、生物标志物、模型 系统、扰动和验证），这将有助于推动该领域的发展。 解决所有这些领域的多学科团队，特别是作为组织绘图中心 (TMC)，将重点关注 生成细胞衰老和相关组织环境的分子和细胞图谱 4 具体来说，它将 (a) 收集、分析、注释和共享高值。 优质无病人类原发性（骨髓和胸腺）和继发性（扁桃体和淋巴结） 淋巴组织，（2）开发和部署一套高分辨率、高含量和高通量的单- 细胞和空间组学技术来表征这些样本和配对的生物流体，并且（3）执行 综合信息学来识别衰老细胞异质性的生物标志物并构建综合信息 这些器官中细胞衰老和相关环境的分子和细胞图谱。 生物分析流程包括：(1) 单细胞高重 (>40) 蛋白质分泌组分析，(2) 单细胞 蛋白质转录组测序（scCITE-seq），（3）细胞水平的空间蛋白质转录组测序 （DBiT-seq 用于在细胞水平上以 10μm 像素共同绘制整个转录组和一组约 300 种蛋白质 大小），以及 (4) FFPE 组织中约 1,000 个分子靶标的单分子空间分子成像 (SMI) 借助这些独特的工具，我们将 (a) 表征功能 SASP 异质性和 识别不同细胞类型中 SAPS 的生物标志物，(b) 在 4 个人中构建分子和细胞图谱 淋巴组织，以及（c）识别组织和相关环境中细胞衰老的生物标志物， 为 SenNet 的资源建设做出贡献，因为免疫功能是所有人生理学的核心。 主要器官，我们的研究将深入了解衰老免疫细胞在发育、衰老或 肠道、肺、肝脏和肾脏等其他器官的疾病，代表了 SenNet 和 更广泛的科学界。