Minnesota Tissue Mapping Center for Senescent Cells

项目摘要 已知衰老细胞（SnCs）在衰老和许多与年龄相关的疾病中发挥因果作用。然而，在这方面， 它们还有助于伤口愈合和组织重塑。生理和病理作用都是相互联系的 SnCs的分泌组及其与免疫系统的复杂相互作用，这被认为是发挥作用的关键。 在清除SnCs方面发挥重要作用。我们对SnCs的大部分了解都来自小鼠， 已经清楚地证明，在衰老或患病的生物体中遗传或药理学去除SnC 减少虚弱;提高力量，耐力和弹性;并减少各种与年龄有关的疾病 包括老年痴呆症这种新的治疗方法靶向一个共同的基本衰老过程， 许多疾病-而不是药物治疗疾病特异性扰动（例如，低胰岛素或高血压）-可能 对我们的老龄化人口有着巨大的影响。然而，关于人类的SnCs， 安全有效地部署这些方法。该项目旨在建立一个组织绘图中心， 明尼苏达大学（MN TMC）为SenNet联盟做出贡献，该联盟打算建立一个4D地图集， SnCs在多个人体器官中的健康老化。MN TMC建议重点关注脂肪（网膜和 皮下）、骨骼肌（股外侧肌）、肝脏和卵巢组织。此选择基于MN TMC的 这些器官的生物学、细胞生物学和免疫学方面的专业知识;研究这些器官中的SnC;以及 在这些器官中使用单细胞技术的经验。MN TMC及其行政核心将由以下人员领导： 具有SnCs和计算生物学/健康信息学互补专业知识的PI。生物标本核心 将由UMN外科主席和一位有成就的病理学家领导。生物分析核心将 由SnC专家和UMN领导空间基因组学的分子病理学家领导。数据分析 核心将由三名生物信息学家领导，他们在建模，单细胞和空间组学分析方面具有专业知识， 将患者电子健康记录与组学数据混合。所提出的MN TMC的独特特征在于， 整个工作流程将容纳在现有的基础设施/核心内：从CTSI和BioNet，管理 人类受试者研究、组织采购、注释和分发/存储，到基因组/ 蛋白质组学/成像核心，沿着与健康信息学研究所一起进行数据管理和多路复用。 主要人员包括所有这些UMN组成部分的领导。这种方法提供了无与伦比的稳定性 我们的分析管道和到位的质量控制和保证机制。第二个独特的特点是 拟议的MN TMC是我们在福尔马林固定的石蜡上进行空间转录组学和蛋白质组学的能力 嵌入式生物标本，可分析最稳定的生物标本和几乎所有存档的 材料总的来说，MN TMC的目标是对人类SnC的4D图谱做出重大贡献， 与NIH和其他TMC密切合作，开发并遵守SenNet联盟创建的标准。

Project Summary Senescent cells (SnCs) are known to play a causal role in aging and numerous age-related diseases. However, they also contribute to wound healing and tissue remodeling. Both physiological and pathological roles are linked to the secretome of SnCs and their complex interaction with the immune system, which is thought to play an important role in clearing SnCs. Most of what we have learned about SnCs is derived from mice where it has been clearly demonstrated that genetic or pharmacologic removal of SnCs in aged or diseased organisms reduces frailty; improves strength, endurance, and resilience; and attenuates a variety of age-related diseases including Alzheimer’s. This novel approach of therapeutically targeting a fundamental aging process common to many diseases – rather than drugging disease-specific perturbations (e.g., low insulin or hypertension) – could have a tremendous impact on our aging population. However, much needs to be learned about SnCs in humans to deploy such approaches safely and effectively. This project aims to establish a Tissue Mapping Center at the University of Minnesota (MN TMC) to contribute to the SenNet Consortium, which intends to build a 4D atlas of SnCs in multiple human organs with healthy aging. MN TMC proposes to focus on adipose (omental and subcutaneous), skeletal muscle (Vastus lateralis), liver, and ovarian tissue. This selection is based on MN TMC’s expertise in the biology, cell biology, and immunology of these organs; in studying SnCs in these organs; and experience with single cell technologies in these organs. The MN TMC and its Administrative Core will be led by PIs with complementary expertise in SnCs and computational biology/health informatics. The Biospecimen Core will be led by the UMN Chairman of Surgery and an accomplished pathologist. The Biological Analysis Core will be led by an expert in SnC and a molecular pathologist leading spatial genomics at UMN. The Data Analysis Core will be led by three bioinformaticians with expertise in modeling, single cell, and spatial-omics analysis, and blending patient electronic health records with -omics data. A unique feature of the proposed MN TMC is that the entire workflow will be housed within existing infrastructure/cores: from CTSI and BioNet, which manage human subjects research, tissue procurement, annotation, and distribution/storage, to the genomic/ proteomics/imaging cores, along with the Institute of Health Informatics for data management and multiplexing. Key personnel include leadership of all of these UMN components. This approach provides unequaled stability of our analytical pipeline and in-place quality control and assurance mechanisms. A second unique feature of the proposed MN TMC is our ability to perform spatial transcriptomics and proteomics on formalin-fixed paraffin embedded biospecimens, which enables analysis of the most stable biospecimens and virtually any archived material. Overall, the goal of the MN TMC is to make a significant contribution to the 4D atlas of human SnCs, working closely with NIH and other TMCs to develop and adhere to standards created by the SenNet Consortium.