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

项目概要/摘要 细胞衰老的特征是细胞周期的不可逆停滞，同时伴随着细胞内分泌的抑制。 可以深刻影响组织微环境的程序。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。相关信号通路的研究， 缺乏人体组织中细胞随时间衰老的潜在机制。我们利用 组学和分子成像技术的最新进展使我们能够研究转录 在更高的深度和分辨率下驱动衰老和/或与衰老相关的变化和分泌特征 比以往任何时候都多在这里，我们建议发展华盛顿大学衰老组织绘图中心 （WU-SN-TMC）。我们的WU-SN-TMC将开发蜂窝 衰老图谱使用来自四种基本组织类型的500个人类样本：骨髓，乳腺， 结肠和肝脏我们将首先优化我们的组学和成像技术和平台， 检测、表征和可视化衰老细胞;开发计算工具和模型， 衰老细胞和标记物鉴定;构建乳腺、骨髓、结肠和肝脏衰老 地图集在空间和时间的背景下，并评估景观和衰老的异质性。与 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， 生物标志物，并研究衰老细胞和细胞周期之间的相互作用。 衰老相关的微环境最后，我们将与其他SenNet中心合作， 通过对所有SenNet的综合和比较研究， 跨组织类型、时间、性别、年龄和祖先组的数据。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，包括批量蛋白质基因组学、单细胞 测序，空间转录组学，CODEX分子成像，3D光片显微镜加上扩展 在资助期内可能成熟的技术，如单分子测序， 高分辨率、多参数生物标志物和所选四种组织类型的细胞衰老图。 我们拥有完善的基础设施和专业知识来成功开展这项工作，包括高质量的 生物标本采集、组学和成像数据生成、实验确认和验证，以及高 高通量、标准化和可重复的数据分析。总之，我们将与其他SenNet公司密切合作， 联合组织和数据协调中心（CODCC），以生成全面的 各种生理条件下主要人体组织类型的图谱，包括 人类寿命

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.