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; 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 人体组织中的细胞感应是一种不可逆的细胞周期停滞状态，原本增殖的细胞中，它 是衰老的标志，可以通过感应相关的秘书表型来改变组织环境 （SASP），但也可能在组织重塑，再生和伤口愈合中起有益的作用。淋巴样 器官在造血和免疫功能中起着至关重要的作用。这些组织中的细胞感受如何 与应力诱导或与年龄相关的功能障碍相关，感觉细胞的类型或亚型 存在且它们的空间异质性以及这些细胞如何影响组织环境保持较差 理解，排除靶向感觉细胞以改善健康范围/寿命的策略的制定 或利用这些细胞或分泌因素促进组织重塑和修复。最近的评论 NIH发表在细胞中，确定了五个广泛的区域（地图集，成像和可视化，生物标志物，模型 系统，扰动和验证）将有助于推动该领域的前进。我们的申请将组装 多学科团队应对所有这些领域，具体来说，作为组织地图中心（TMC），将集中精力 在生成4个细胞感应和相关组织环境的分子图和细胞图时 一级和继发性淋巴器官。具体而言，它将（a）收集，分析，注释和分享高 质量非固定人类原发性（骨髓和胸腺）和次级（扁桃体和淋巴结） 淋巴组织，（2）开发和部署一套高分辨率，高通量和高通量单一的 细胞和空间法技术以表征这些物种和成对的生物流体，并且（3）执行 综合信息，以识别感觉细胞异质性的生物标志物并构建全面 这些器官中细胞感应和相关环境的分子图和细胞图。四个专业 生物分析管道是：（1）单细胞高质量（> 40）蛋白质分泌物分析，（2）单细胞 蛋白转录组测序（SCCITE-SEQ），（3）在细胞水平上的空间蛋白转录测序 （用于共映射整个转录组的DBIT-SEQ和一个〜300蛋白在细胞水平上的〜300蛋白，带有10µm像素 尺寸）和（4）在单分子的FFPE组织中〜1,000个分子靶标的空间分子成像（SMI） 亚细胞分辨率。使用这些独特的工具，我们将（a）表征功能性SASP异质性和 在不同的细胞类型中识别SAPS的生物标志物，（b）在4人类中构建分子和细胞图 淋巴组织，（c）鉴定组织和相关环境中细胞感应的生物标志物， 为Sennet的资源建设做出贡献。由于免疫功能是所有人的生理学的核心 主要器官，我们的研究将为感觉免疫细胞在发育，衰老或 肠道，肺，肝和肾脏等其他器官的疾病，代表Sennet和 广泛的科学界。