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.

项目摘要 人体组织中的细胞衰老是在其他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。淋巴 器官在造血和免疫功能中起着至关重要的作用。这些组织中的细胞衰老 与应激诱导或年龄相关的功能障碍有关，衰老细胞的类型或亚型 并且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，排除了针对衰老细胞以改善健康寿命/寿命的策略的发展 或利用这些细胞或分泌的因子来促进组织重塑和修复。最近一篇评论 NIH在Cell上发表的论文确定了五个广泛的领域（地图集、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向前发展。我们的应用程序将组装一个 多学科团队来解决所有这些领域，特别是作为一个组织映射中心（TMC），将重点 在4中生成细胞衰老和相关组织环境的分子和细胞图 初级和次级淋巴器官。具体而言，它将（a）收集，分析，注释和分享高 优质非病变人原发性（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，以及（3）执行 整合信息学，以确定衰老细胞异质性的生物标志物，并构建全面的 这些器官中细胞衰老和相关环境的分子和细胞图谱。四大 生物分析管道是：（1）单细胞高重（>40）蛋白质分泌组谱，（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像素共映射整个转录组和一组约300种蛋白质 大小），和（4）FFPE组织中约1，000个分子靶点的单分子空间分子成像（SMI） 亚细胞分辨率有了这些独特的工具，我们将（a）表征功能性SASP异质性， 鉴定不同细胞类型中SAPS生物标志物，（B）在4个人中构建分子和细胞图谱 淋巴组织，和（c）鉴定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。由于免疫功能是所有人生理学的核心， 我们的研究将为衰老免疫细胞在发育、衰老或衰老过程中的作用提供见解。 疾病在其他器官，如肠道，肺，肝脏和肾脏，代表了强大的协同作用，在SenNet和 更广泛的科学界。