Washington University Senescence Tissue Mapping Center (WU-SN-TMC)

总体项目摘要/摘要 细胞衰老的特征是一种不可逆转的细胞周期停滞状态，伴随着一种分泌 可以对组织微环境产生深远影响的程序。我们目前对衰老的理解是 主要基于细胞培养和基于模型的研究。相关信号转导途径及研究进展 随着时间的推移，人体组织中细胞衰老的潜在机制尚不清楚。我们的杠杆能力 组学和分子成像技术的最新进展使我们能够研究转录 推动和/或与更高深度和分辨率的衰老相关的变化和分泌特征 比以往任何时候都要好。在这里，我们建议开发华盛顿大学衰老组织测绘中心 (WU-SN-TMC)在NIH衰老网络(Sennet)内。我们的WU-SN-TMC将发展成细胞化 使用来自四种基本组织类型的500份人体样本绘制的衰老图谱：骨髓，乳房， 结肠和肝脏。我们将首先优化我们的组学和成像技术以及捕获、 检测、表征和可视化衰老细胞；开发计算工具和模型，以准确地 衰老细胞和标志物的鉴定；构建乳房、骨髓、结肠和肝脏衰老 空间和时间背景下的地图集；以及评估衰老的景观和异质性。使用 这些初始图谱，我们将进一步表征、验证和定义细胞衰老表型和 利用摄动方法研究衰老细胞与细胞之间的相互作用 与衰老相关的微环境。最后，我们将与其他Sennet中心合作建立 综合比较研究所有老年人的综合主要器官/组织衰老图谱 跨组织类型、时间、性别、年龄和血统群体的数据。作为Sennet计划的成员，Wu-SN- TMC将采用最先进的组学和成像技术，包括批量蛋白质组学、单细胞 测序、空间转录学、食典分子成像、3D光片显微镜和扩张术 可能在资助期内成熟的技术，如单分子测序，以产生 高分辨率、多参数生物标志物和选定的四种组织类型的细胞衰老地图。 我们拥有成功开展这项工作的既定基础设施和专业知识，包括高质量 生物样品的收集、组学和成像数据的产生、实验确认和验证，以及高 吞吐量、标准化和可重复性的数据分析。总之，我们将与其他Sennet密切合作 中心和联合体组织和数据协调中心(CODCC)，以产生全面的 不同生理条件下主要人体组织类型的图谱，包括 人的寿命。

Overall Project Summary/Abstract Cellular senescence has been characterized as a state of irreversible cell-cycle arrest coupled with a secretory program that can profoundly impact the tissue microenvironment. Our current understanding of senescence is largely based on cell culture and model-based studies. Research on the relevant signaling pathways and mechanisms underlying cellular senescence across human tissues over time is lacking. Our ability to leverage recent advances in omics and molecular imaging technologies enables us to investigate the transcriptional changes and secretory features driving and/or associated with senescence at higher depths and resolution than ever before. Here, we propose to develop the Washington University Senescence Tissue Mapping Center (WU-SN-TMC) within the NIH Senescence Network (SenNet). Our WU-SN-TMC will develop cellular senescence atlases using 500 human samples from four essential tissue types: bone marrow, breast, colon, and liver. We will first optimize our omics and imaging technologies and platforms for capturing, detecting, characterizing, and visualizing senescent cells; develop computational tools and models for accurate identification of senescent cells and markers; construct breast, bone marrow, colon, and liver senescence atlases in spatial and temporal contexts; and assess the landscape and heterogeneity of senescence. With these initial atlases, we will further characterize, validate, and define cellular senescence phenotypes and biomarkers using perturbation methods and investigate the interactions between senescent cells and the senescence-associated microenvironment. Finally, we will work with other SenNet centers to build comprehensive, major organ/tissue senescence atlases by integrated and comparative studies of all SenNet data across tissue types, time, sex, age, and ancestry groups. As a member of the SenNet program, WU-SN- TMC will employ state-of-the-art omics and imaging technologies, including bulk proteogenomics, single cell sequencing, spatial transcriptomics, CODEX molecular imaging, 3D light sheet microscopy plus expansion technologies that are likely to mature over the funding period, such as single molecule sequencing, to generate high-resolution, multi-parameter biomarkers and maps of cellular senescence in the four tissue types selected. We have the established infrastructure and expertise to successfully conduct this work, including high quality biospecimen collection, omics and imaging data production, experimental confirmation and validation, and high throughput, standardized, and reproducible data analysis. In conclusion, we will work closely with other SenNet centers and the Consortium Organization and Data Coordination Center (CODCC), to generate comprehensive atlases across major human tissue types under various physiological conditions, including changes across the human lifespan.